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Chen JF, Guo SJ, He B, Zheng W, Jiang WJ, Yuan Z, Xiang Y, Peng C, Xiong W, Shi JY. Advances of dual inhibitors based on ALK for the treatment of cancer. Bioorg Chem 2025; 159:108417. [PMID: 40168884 DOI: 10.1016/j.bioorg.2025.108417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 03/17/2025] [Accepted: 03/25/2025] [Indexed: 04/03/2025]
Abstract
Anaplastic lymphoma kinase (ALK), which encodes a highly conserved receptor tyrosine kinase (RTK), is important for the development and progression of many tumors, especially non-small cell lung cancer (NSCLC). Currently, third-generation ALK inhibitors are used to treat ALK-mutant NSCLC, but the rapid emergence of resistance during treatment greatly limits their efficacy in clinic. In comparison to single-target inhibitors, ALK dual inhibitors offer the benefits of reducing the emergence of drug resistance, improving treatment efficacy, and optimizing pharmacokinetic features due to the synergistic function of ALK and other associated targets involved in tumor progression. Therefore, we outline the development of ALK dual inhibitors, highlight their design approaches and structure-activity relationship (SAR), and offer insights into new challenges and potential future directions in this area.
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Affiliation(s)
- Jin-Feng Chen
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 611731. China; Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Shu-Jin Guo
- Department of Health Management Center, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Bin He
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Wei Zheng
- Department of Integrative Medicine, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
| | - Wen-Jie Jiang
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Zhuo Yuan
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yu Xiang
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Cheng Peng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; State Key Laboratory of Southwestern Chinese Medicine Resources, School of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Wei Xiong
- Department of urology, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, Chengdu 610072, China.
| | - Jian-You Shi
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China.
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2
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Liang H, Huang S, Xu X, Yin Z, Hussain M, Song X, Yi J, He Y, Guo J, Tu Z, Zhang Z, Zhou Y, Lu X. Designing Macrocyclic Kinase Inhibitors Using Macrocycle Scaffold Hopping with Reinforced Learning (Macro-Hop). J Med Chem 2025; 68:6698-6717. [PMID: 40101196 DOI: 10.1021/acs.jmedchem.5c00087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2025]
Abstract
Macrocycles have gained significant attention in drug discovery, with over 70 macrocyclic compounds currently in clinical use. Despite this progress, the effective methods for designing macrocycles remain elusive. In this study, we present Macro-Hop, a reinforced learning framework designed to rapidly and comprehensively explore the macrocycle chemical space. Macro-Hop efficiently generates novel macrocyclic scaffolds that not only align with predefined physicochemical properties but also exhibit 3D structural similarities to a specified reference compound. As a proof of concept, we applied Macro-Hop to design a new series of macrocycle inhibitors targeting PDGFRαD842 V kinase. The representative compound L7 exhibited high potency against PDGFRαD842 V in both biochemical and cellular assays with IC50 values of 23.8 and 2.1 nM, respectively. L7 effectively inhibited clinically relevant secondary mutants PDGFRαD842 V/G680R (IC50 = 64.1 nM) and PDGFRαD842 V/T674I (IC50 = 27.6 nM), highlighting the rapid effectiveness of wet-leb validation with Macro-Hop.
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Affiliation(s)
- Hong Liang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Shengjie Huang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Xinxin Xu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Zhao Yin
- Department of Hematology, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, Guangdong Province 510317, China
| | - Muzammal Hussain
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, New York 10016, United States
| | - Xiaojuan Song
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Jianqiao Yi
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Yingqi He
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Jing Guo
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Zhengchao Tu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Zhang Zhang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Yang Zhou
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Xiaoyun Lu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China
- Department of Hematology, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, Guangdong Province 510317, China
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3
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AlKhazal A, Chohan S, Ross DJ, Kim J, Brown EG. Emerging clinical and research approaches in targeted therapies for high-risk neuroblastoma. Front Oncol 2025; 15:1553511. [PMID: 40104501 PMCID: PMC11913827 DOI: 10.3389/fonc.2025.1553511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 02/06/2025] [Indexed: 03/20/2025] Open
Abstract
Neuroblastoma is a pediatric cancer that originates from neural crest cells and is the most common extracranial solid tumor in children under five years of age. While low-risk neuroblastoma often regresses spontaneously, high-risk neuroblastoma poses a significant clinical challenge. Recent advances in understanding neuroblastoma's molecular mechanisms have led to the development of targeted therapies that aim to selectively inhibit specific pathways involved in tumor growth and progression, improving patient outcomes while minimizing side effects. This review provides a comprehensive review of neuroblastoma biology and emerging therapeutic strategies. Key topics include (a) immunotherapies and immunotargets, (b) non-coding RNAs (long non-coding RNA, microRNA, and circular RNA), (c) molecular biomarkers and pathways, and (d) limitations and future directions.
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Affiliation(s)
- Albatool AlKhazal
- Department of Surgery, School of Medicine, University of California, Davis, Davis, CA, United States
| | - Samiha Chohan
- Department of Surgery, School of Medicine, University of California, Davis, Davis, CA, United States
- Department of Biological Sciences, California State University, Sacramento, Sacramento, CA, United States
| | - Destani J Ross
- Department of Surgery, School of Medicine, University of California, Davis, Davis, CA, United States
| | - Jinhwan Kim
- Department of Surgery, School of Medicine, University of California, Davis, Davis, CA, United States
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, United States
| | - Erin G Brown
- Department of Surgery, School of Medicine, University of California, Davis, Davis, CA, United States
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4
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Waliany S, Lin JJ, Gainor JF. Evolution of first versus next-line targeted therapies for metastatic non-small cell lung cancer. Trends Cancer 2025; 11:245-257. [PMID: 39890507 DOI: 10.1016/j.trecan.2025.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 12/21/2024] [Accepted: 01/10/2025] [Indexed: 02/03/2025]
Abstract
The expanding armamentarium of targeted therapies has revolutionized treatment for metastatic oncogene-addicted lung cancers. For multiple subsets, such as those harboring EGFR mutations and fusions in ALK or ROS1, successive generation of increasingly potent, selective, and brain-penetrating targeted therapies have shifted the treatment paradigm towards preferential first-line use of next-generation drugs. This evolution in clinical practice provides a lens through which to review the lessons learned from drug development in oncogene-addicted lung cancers, guided by translational insights into tumor biology and mechanisms of therapeutic resistance. For oncogenic drivers that are less sensitive to single-agent targeted therapies, rationally designed combination strategies will be needed to enable first-line use of targeted agents.
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Affiliation(s)
- Sarah Waliany
- Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Jessica J Lin
- Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Justin F Gainor
- Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
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5
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Chugh S, Tien JC, Hon J, Kenum C, Mannan R, Cheng Y, Li CC, Taher ZI, Delekta AD, Bawa PS, Apel IJ, Miner SJ, Cao X, Mehra R, Dhanasekaran SM, Qiao Y, Mody R, Chinnaiyan AM. Therapeutic benefit of the dual ALK/FAK inhibitor ESK440 in ALK-driven neuroblastoma. Neoplasia 2025; 60:100964. [PMID: 39900433 PMCID: PMC11846495 DOI: 10.1016/j.neo.2024.100964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 01/02/2024] [Indexed: 02/05/2025]
Abstract
Neuroblastoma (NB) is a predominantly pediatric cancer with greater than 90% of cases arising in children under the age of five. More than half of patients have metastases detected at diagnosis, and high-risk disease is associated with five-year survival rates of only 50-60 %. Standard therapy involves highly toxic chemotherapy, surgery, radiation, and immunotherapy, and less toxic, more specific targeted therapies are urgently needed. Genomic studies have identified common driver aberrations in high-risk NB, such as MYCN amplification. In addition, a proportion of high-risk patients harbor amplification or activating mutations in anaplastic lymphoma kinase (ALK), and co-occurrence of ALK mutations and MYCN amplification have been associated with aggressive disease. In this study, we analyzed the efficacy of a Phase Ia-cleared, orally bioavailable dual ALK and focal adhesion kinase (FAK) inhibitor, ESK440, in multiple preclinical NB models. ESK440 potently inhibited proliferation of NB cell lines, with increased sensitivity in cell lines harboring ALK aberrations. ALK, FAK, and downstream target activation were rapidly decreased upon ESK440 treatment, and this was associated with impaired cellular migration and invasion. Importantly, ESK440 treatment also decreased MYCN levels. NB cell line and patient-derived xenograft studies showed significant reduction in tumor growth in ESK440-treated mice with no signs of toxicity. In certain NB models, ESK440 showed comparable or enhanced efficacy to lorlatinib, another clinical ALK inhibitor, and a lorlatinib-resistant cell line (COG-N-561 LR) retained sensitivity to ESK440. These preclinical results indicate that ESK440 is a promising targeted agent for ALK-driven NB and support future clinical studies to evaluate its efficacy in NB patients.
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Affiliation(s)
- Seema Chugh
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jean C Tien
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jennifer Hon
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Carson Kenum
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Rahul Mannan
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yunhui Cheng
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Chi Chiang Li
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Zainab I Taher
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Andrew D Delekta
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Pushpinder Singh Bawa
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Ingrid J Apel
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Stephanie J Miner
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Xuhong Cao
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Rohit Mehra
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Saravana M Dhanasekaran
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yuanyuan Qiao
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Rajen Mody
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Arul M Chinnaiyan
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
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6
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Yang Y, Yang H, Gao Y, Yang Q, Zhu X, Miao Q, Xu X, Li Z, Zuo D. EML4-ALK G1202R and EML4-ALK L1196M mutations induce crizotinib resistance in non-small cell lung cancer cells through activating epithelial-mesenchymal transition mediated by MDM2/MEK/ERK signal axis. Cell Biol Int 2025; 49:55-67. [PMID: 39318039 DOI: 10.1002/cbin.12249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 08/04/2024] [Accepted: 09/13/2024] [Indexed: 09/26/2024]
Abstract
Crizotinib, as the first-generation of anaplastic lymphoma kinase (ALK) inhibitor, effectively improves the survival time of ALK-positive non-small cell lung cancer (NSCLC) patients. However, its efficacy is severely limited by drug resistance caused by secondary mutations. G1202R and L1196M are classical mutation sites located in ALK kinase domain. They may hinder the binding of ALK inhibitors to the target kinase domain, resulting in drug resistance in patients. However, the exact mechanism of drug resistance mediated by these mutations remains unclear. In this study, we aimed to evaluate how G1202R and L1196M mutations mediate crizotinib resistance. To explore the resistance mechanism, we constructed EML4-ALK G1202R and L1196M mutant cell lines with A549 cells. The results showed that the mutant cells exhibited significant epithelial-mesenchymal transition (EMT) and metastasis compared to control (A549-vector) or wild type (A549-EML4-ALK) cells. Subsequently, it was found that the occurrence of EMT was correlated to the high expression of murine double minute 2 (MDM2) protein and the activation of mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway in mutant cells. Down-regulation of MDM2 inhibited the activation of MEK/ERK pathway, thus reversed the EMT process and markedly increased the inhibitory effect of crizotinib on the growth of mutant cells. Collectively, resistance of ALK-positive NSCLC cells to crizotinib is induced by G1202R and L1196M mutations through activation of the MDM2/MEK/ERK signalling axis, promoting EMT process and metastasis. These findings suggest that the combination of MDM2 inhibitors and crizotinib could be a potential therapeutic strategy.
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MESH Headings
- Crizotinib/pharmacology
- Humans
- Epithelial-Mesenchymal Transition/drug effects
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/metabolism
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/pathology
- Proto-Oncogene Proteins c-mdm2/metabolism
- Proto-Oncogene Proteins c-mdm2/genetics
- Drug Resistance, Neoplasm/genetics
- Drug Resistance, Neoplasm/drug effects
- Lung Neoplasms/drug therapy
- Lung Neoplasms/metabolism
- Lung Neoplasms/genetics
- Lung Neoplasms/pathology
- Oncogene Proteins, Fusion/metabolism
- Oncogene Proteins, Fusion/genetics
- MAP Kinase Signaling System/drug effects
- Mutation
- Animals
- A549 Cells
- Cell Line, Tumor
- Mice, Nude
- Mice
- Protein Kinase Inhibitors/pharmacology
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Affiliation(s)
- Yuying Yang
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Huan Yang
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Yunhui Gao
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Qian Yang
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Xinya Zhu
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Qianying Miao
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Xiaobo Xu
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Zengqiang Li
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Daiying Zuo
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
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7
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Wu D, Sun Q, Tang H, Xiao H, Luo J, Ouyang L, Sun Q. Acquired resistance to tyrosine kinase targeted therapy: mechanism and tackling strategies. Drug Resist Updat 2025; 78:101176. [PMID: 39642660 DOI: 10.1016/j.drup.2024.101176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 11/21/2024] [Accepted: 11/23/2024] [Indexed: 12/09/2024]
Abstract
Over the past two decades, tyrosine kinase inhibitors (TKIs) have rapidly emerged as pivotal targeted agents, offering promising therapeutic prospects for patients. However, as the cornerstone of targeted therapies, an increasing number of TKIs have been found to develop acquired resistance during treatment, making the challenge of overcoming this resistance a primary focus of current research. This review comprehensively examines the evolution of TKIs from multiple perspectives, with particular emphasis on the mechanisms underlying acquired resistance, innovative drug design strategies, inherent challenges, and future directions.
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Affiliation(s)
- Defa Wu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu 610041, China
| | - Qian Sun
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu 610041, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, China; West China Medical Publishers, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Haolin Tang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu 610041, China
| | - Huan Xiao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu 610041, China
| | - Jiaxiang Luo
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu 610041, China
| | - Liang Ouyang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu 610041, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, China.
| | - Qiu Sun
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu 610041, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, China; West China Medical Publishers, West China Hospital, Sichuan University, Chengdu 610041, China.
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8
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Bearz A, Bertoli E, Stanzione B, De Carlo E, Del Conte A, Bortolot M, Torresan S, Berto E, Da Ros V, Pelin GM, Fassetta K, Rossetto S, Spina M. EML4-ALK: Update on ALK Inhibitors. Int J Mol Sci 2025; 26:308. [PMID: 39796163 PMCID: PMC11719670 DOI: 10.3390/ijms26010308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 12/29/2024] [Accepted: 12/30/2024] [Indexed: 01/13/2025] Open
Abstract
Since the discovery of the first-generation ALK inhibitor, many other tyrosine kinase inhibitors have been demonstrated to be effective in the first line or further lines of treatment in patients with advanced non-small cell lung cancer with EMLA4-ALK translocation. This review traces the main milestones in the treatment of ALK-positive metastatic patients and the survival outcomes in the first-line and second-line settings with different ALK inhibitors. It presents the two options available for first-line treatment at the present time: sequencing different ALK inhibitors versus using the most potent inhibitor in front-line treatment. The efficacy outcomes of different ALK inhibitors in the first-line setting; the molecular profile of the disease, including mutation resistances and ALK variants and co-mutations; and patients' co-morbidities and inhibitor toxicities should be taken into account to address the choice of the first-line treatment, as suggested in this review.
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Affiliation(s)
- Alessandra Bearz
- Centro di Riferimento Oncologico di Aviano (CRO), National Cancer Institute, IRCCS, 33081 Aviano, Italy; (E.B.); (A.D.C.); (G.M.P.); (S.R.)
| | - Elisa Bertoli
- Centro di Riferimento Oncologico di Aviano (CRO), National Cancer Institute, IRCCS, 33081 Aviano, Italy; (E.B.); (A.D.C.); (G.M.P.); (S.R.)
| | - Brigida Stanzione
- Centro di Riferimento Oncologico di Aviano (CRO), Department of Medical Oncology, IRCCS, 33081 Aviano, Italy; (B.S.); (E.D.C.); (E.B.); (V.D.R.); (K.F.); (M.S.)
| | - Elisa De Carlo
- Centro di Riferimento Oncologico di Aviano (CRO), Department of Medical Oncology, IRCCS, 33081 Aviano, Italy; (B.S.); (E.D.C.); (E.B.); (V.D.R.); (K.F.); (M.S.)
| | - Alessandro Del Conte
- Centro di Riferimento Oncologico di Aviano (CRO), National Cancer Institute, IRCCS, 33081 Aviano, Italy; (E.B.); (A.D.C.); (G.M.P.); (S.R.)
| | - Martina Bortolot
- Centro di Riferimento Oncologico di Aviano (CRO), Department of Medical Oncology, IRCCS, 33081 Aviano, Italy; (B.S.); (E.D.C.); (E.B.); (V.D.R.); (K.F.); (M.S.)
- Department of Medicine, University of Udine, 33100 Udine, Italy
| | - Sara Torresan
- Centro di Riferimento Oncologico di Aviano (CRO), Department of Medical Oncology, IRCCS, 33081 Aviano, Italy; (B.S.); (E.D.C.); (E.B.); (V.D.R.); (K.F.); (M.S.)
- Department of Medicine, University of Udine, 33100 Udine, Italy
| | - Eleonora Berto
- Centro di Riferimento Oncologico di Aviano (CRO), Department of Medical Oncology, IRCCS, 33081 Aviano, Italy; (B.S.); (E.D.C.); (E.B.); (V.D.R.); (K.F.); (M.S.)
| | - Valentina Da Ros
- Centro di Riferimento Oncologico di Aviano (CRO), Department of Medical Oncology, IRCCS, 33081 Aviano, Italy; (B.S.); (E.D.C.); (E.B.); (V.D.R.); (K.F.); (M.S.)
| | - Giulia Maria Pelin
- Centro di Riferimento Oncologico di Aviano (CRO), National Cancer Institute, IRCCS, 33081 Aviano, Italy; (E.B.); (A.D.C.); (G.M.P.); (S.R.)
| | - Kelly Fassetta
- Centro di Riferimento Oncologico di Aviano (CRO), Department of Medical Oncology, IRCCS, 33081 Aviano, Italy; (B.S.); (E.D.C.); (E.B.); (V.D.R.); (K.F.); (M.S.)
| | - Silvia Rossetto
- Centro di Riferimento Oncologico di Aviano (CRO), National Cancer Institute, IRCCS, 33081 Aviano, Italy; (E.B.); (A.D.C.); (G.M.P.); (S.R.)
| | - Michele Spina
- Centro di Riferimento Oncologico di Aviano (CRO), Department of Medical Oncology, IRCCS, 33081 Aviano, Italy; (B.S.); (E.D.C.); (E.B.); (V.D.R.); (K.F.); (M.S.)
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Masciale V, Banchelli F, Grisendi G, Samarelli AV, Raineri G, Rossi T, Zanoni M, Cortesi M, Bandini S, Ulivi P, Martinelli G, Stella F, Dominici M, Aramini B. The molecular features of lung cancer stem cells in dedifferentiation process-driven epigenetic alterations. J Biol Chem 2024; 300:107994. [PMID: 39547513 PMCID: PMC11714729 DOI: 10.1016/j.jbc.2024.107994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 10/30/2024] [Accepted: 11/05/2024] [Indexed: 11/17/2024] Open
Abstract
Cancer stem cells (CSCs) may be dedifferentiated somatic cells following oncogenic processes, representing a subpopulation of cells able to promote tumor growth with their capacities for proliferation and self-renewal, inducing lineage heterogeneity, which may be a main cause of resistance to therapies. It has been shown that the "less differentiated process" may have an impact on tumor plasticity, particularly when non-CSCs may dedifferentiate and become CSC-like. Bidirectional interconversion between CSCs and non-CSCs has been reported in other solid tumors, where the inflammatory stroma promotes cell reprogramming by enhancing Wnt signaling through nuclear factor kappa B activation in association with intracellular signaling, which may induce cells' pluripotency, the oncogenic transformation can be considered another important aspect in the acquisition of "new" development programs with oncogenic features. During cell reprogramming, mutations represent an initial step toward dedifferentiation, in which tumor cells switch from a partially or terminally differentiated stage to a less differentiated stage that is mainly manifested by re-entry into the cell cycle, acquisition of a stem cell-like phenotype, and expression of stem cell markers. This phenomenon typically shows up as a change in the form, function, and pattern of gene and protein expression, and more specifically, in CSCs. This review would highlight the main epigenetic alterations, major signaling pathways and driver mutations in which CSCs, in tumors and specifically, in lung cancer, could be involved, acting as key elements in the differentiation/dedifferentiation process. This would highlight the main molecular mechanisms which need to be considered for more tailored therapies.
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Affiliation(s)
- Valentina Masciale
- Laboratory of Cellular Therapies, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Federico Banchelli
- Department of Statistical Sciences "Paolo Fortunati", Alma Mater Studiorum- University of Bologna, Bologna, Italy
| | - Giulia Grisendi
- Laboratory of Cellular Therapies, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Anna Valeria Samarelli
- Laboratory of and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Giulia Raineri
- Laboratory of Cellular Therapies, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Tania Rossi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Michele Zanoni
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Michela Cortesi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Sara Bandini
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Paola Ulivi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Giovanni Martinelli
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Franco Stella
- Thoracic Surgery Unit, Department of Medical and Surgical Sciences-DIMEC of the Alma Mater Studiorum, University of Bologna, G.B. Morgagni-L. Pierantoni Hospital, Forlì, Italy
| | - Massimo Dominici
- Laboratory of Cellular Therapies, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy; Division of Oncology, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena, Italy
| | - Beatrice Aramini
- Thoracic Surgery Unit, Department of Medical and Surgical Sciences-DIMEC of the Alma Mater Studiorum, University of Bologna, G.B. Morgagni-L. Pierantoni Hospital, Forlì, Italy.
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10
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Wang Z, Luo Y, Gong H, Chen Y, Tang H. A novel double fusion of EML4-ALK and PLEKHA7-ALK contribute to rapid progression of lung adenocarcinoma: a case report and literature review. Discov Oncol 2024; 15:638. [PMID: 39522087 PMCID: PMC11551082 DOI: 10.1007/s12672-024-01517-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024] Open
Abstract
A 40-year-old male with EML4-ALK (E6:A20) fusion variant 3 and previously unreported PLEKHA7-ALK (P3:A20) fusion in lung adenocarcinoma exhibited resistance to alectinib and chemotherapy. Subsequent next-generation sequencing (NGS) from the plasma specimen revealed the co-existing mutation in the KEAP1 gene, which may represent an intrinsic resistance to ALK-TKI. Furthermore, the presence of double fusion PLEKHA7-ALK (P3:A20) may also have played a critical role in the resistance to alectinib. KEAP1 mutation (p.E244K) was also founded in this patient which may lead to resistance to standard chemotherapy. The patient was then treated with brigatinib, which effectively halted the rapid progression. Unfortunately, the patient deceased to uncontrollable, rapidly progressing pleural effusion and pulmonary embolism, resulting in an overall survival of 9 months. This represents the rare case of NSCLC with a double fusion of EML4-ALK and PLEKHA7-ALK, exhibiting resistance to alectinib and chemotherapy. Our case suggests that the double fusion of EML4-ALK and PLEKHA7-ALK and co-existing KEAP1 mutation may serve as an adverse prognostic factor. Additionally, brigatinib may offer a potential treatment option for lung adenocarcinoma patients with PLEKHA7-ALK (P3:A20) fusion.
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Affiliation(s)
- Zhongzhao Wang
- Department of Respiratory and Critical Care Medicine, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China
| | - Yang Luo
- School of Basic Medicine, Naval Medical University, Shanghai, 200433, China
| | - Heng Gong
- School of Basic Medicine, Naval Medical University, Shanghai, 200433, China
| | - Yang Chen
- Department of Respiratory and Critical Care Medicine, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China.
| | - Hao Tang
- Department of Respiratory and Critical Care Medicine, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China.
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11
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Igawa Y, Yoshida T, Makihara R, Torasawa M, Tateishi A, Matsumoto Y, Shinno Y, Okuma Y, Goto Y, Horinouchi H, Yamamoto N, Ohe Y. Association between lorlatinib blood concentration and adverse events and clinical impact of dose modification. Lung Cancer 2024; 196:107954. [PMID: 39303401 DOI: 10.1016/j.lungcan.2024.107954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 09/09/2024] [Accepted: 09/11/2024] [Indexed: 09/22/2024]
Abstract
OBJECTIVES Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, causes distinct adverse events (AEs), including hyperlipidemia and central nervous system (CNS) disorders. Although dose modifications are recommended to manage these AEs, whether dose modifications can achieve optimal blood lorlatinib concentrations and reduce the incidence of lorlatinib-induced AEs remains unclear. Therefore, we investigated the association between lorlatinib exposure and AEs in each patient. MATERIALS AND METHODS We retrospectively reviewed patients with advanced ALK-rearranged non-small cell lung cancer treated with lorlatinib between November 2018 and July 2022. Serum lorlatinib concentrations were assessed using high-performance liquid chromatography-tandem mass spectrometry. All AEs were evaluated using the Common Terminology Criteria for Adverse Events version 5.0. RESULTS The median age of the 55 eligible patients was 59 years (range: 23-79 years). All patients were administered lorlatinib after first line ALK-tyrosine kinase inhibitor failure. Grade ≥ 3 AEs occurred in 25 patients (25/55, 45 %), including hyperlipidemia in 17 (17/55, 31 %), CNS disorders in 7 (7/55, 13 %), and edema in 6 (6/55, 11 %). Dose modification was required in 23 patients (23/55, 42 %). Among the 36 patients with available data on serum lorlatinib levels at day 28 (±14) and no drug dose modifications, lorlatinib serum concentrations were significantly higher in patients with grade ≥ 3 AEs than in those without AEs (median: 462 ng/mL vs. 177 ng/mL, p < 0.01). In eight patients with data on serial lorlatinib serum concentrations following dose modifications, lorlatinib serum concentrations were effectively reduced, facilitating the ongoing administration of lorlatinib. Additionally, no significant difference was observed in the landmark analysis of progression-free survival between patients with dose modification within the first 16 weeks and those without (median: 24.8 months vs. 10.1 months, p = 0.46). CONCLUSION Dose modification of lorlatinib was associated with successful management of AEs and decreased serum concentration of lorlatinib.
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Affiliation(s)
- Yukiko Igawa
- Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
| | - Tatsuya Yoshida
- Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
| | - Reiko Makihara
- Department of Pharmacy, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
| | - Masahiro Torasawa
- Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
| | - Akiko Tateishi
- Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
| | - Yuji Matsumoto
- Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
| | - Yuki Shinno
- Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
| | - Yusuke Okuma
- Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
| | - Yasushi Goto
- Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
| | - Hidehito Horinouchi
- Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
| | - Noboru Yamamoto
- Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
| | - Yuichiro Ohe
- Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
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12
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Dong J, Li L, Deng T, Song H, Zhang S, Zhong M. Interstitial lung disease associated with ALK inhibitors and risk factors: an updated comparative pharmacovigilance analysis. Front Pharmacol 2024; 15:1361443. [PMID: 39399468 PMCID: PMC11466793 DOI: 10.3389/fphar.2024.1361443] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 09/02/2024] [Indexed: 10/15/2024] Open
Abstract
Background Inhibitors of the anaplastic lymphoma kinase (ALK) gene mutation are first-line treatments in patients with ALK-positive lung cancer. The FDA label warns of the risk of interstitial lung disease (ILD) in patients receiving ALK TKIs. However, ILD associated with ALK TKIs is not fully understood. The aim of this study was to characterize the features of ALK TKI-related ILD and to explore risk factors for ALK TKI-related ILD. Methods FDA's Adverse Event Reporting System (FAERS) reports from 2011 Q1 to 2023 Q2 were extracted and combined. Standardized MedDRA queries (SMQs) were used to search for AEs at the preferred term (PT) level. Four algorithms were employed to quantify the signals of ILD associated with ALK TKIs. The risk of ILD was further analyzed using logistic regression. Results A total of 20,064 reports of ALK TKIs and 640 (3.2%) reports of ILD AEs were extracted. Significant disproportionality was detected in all five ALK TKIs. Interstitial lung disease and pneumonitis were the most common lung toxicities induced by ALK TKIs. Results of further analyses revealed a different spectrum of lung toxicity among the various TKIs. The median time to onset of ILD related to ALK TKIs was 53 days (Q1:12, Q3:209), and more than 70% of AEs occurred within the first 2 months. Logistic regression analysis and risk prediction model both showed that different ALK TKIs and their combination with PPIs, amlodipine, and magnesium oxide were independent risk factors for ILD (p<0.05). Conclusion ALK TKIs have different safety profiles regarding lung toxicity, which normally occurs within the first 2 months. Administration in combination with PPIs, amlodipine, and magnesium oxide significantly increases the risk of ILD. These results provide risk prediction for ILD related to ALK TKIs and support pharmacovigilance to promote safe prescribing in oncology.
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Affiliation(s)
- Junli Dong
- Department of Pharmacy, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Pharmacy, Wuhan No.1 hospital, Wuhan, China
| | - Lulu Li
- Department of Pharmacy, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Pharmacy, Wuhan No.1 hospital, Wuhan, China
| | - Tiying Deng
- Department of Pharmacy, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Pharmacy, Wuhan No.1 hospital, Wuhan, China
| | - Haibin Song
- Department of Oncology, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Oncology, Wuhan No.1 hospital, Wuhan, China
| | - Shaohui Zhang
- Department of Pharmacy, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Pharmacy, Wuhan No.1 hospital, Wuhan, China
| | - Minyu Zhong
- Department of Oncology, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Oncology, Wuhan No.1 hospital, Wuhan, China
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13
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Yu L, Yang R, Long Z, Tao Q, Liu B. Targeted therapy of non-small cell lung cancer: mechanisms and clinical trials. Front Oncol 2024; 14:1451230. [PMID: 39391239 PMCID: PMC11464343 DOI: 10.3389/fonc.2024.1451230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 09/09/2024] [Indexed: 10/12/2024] Open
Abstract
Lung cancer is a leading cause of cancer-related deaths globally, and traditional chemotherapy has limited efficacy in treating advanced non-small cell lung cancer (NSCLC). In recent years, the prognosis for patients with NSCLC has significantly improved due to the development of new treatment modalities, including targeted therapies. Targeted therapies utilize monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), or small molecule tyrosine kinase inhibitors (TKIs) directed against specific mutated genes such as EGFR and ALK. The development of these drugs has deepened our understanding of NSCLC and improved treatment outcomes for patients. This review aims to summarize the mechanisms and current status of targeted therapy for NSCLC, discuss strategies to overcome acquired resistance, and address current challenges in the field.
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Affiliation(s)
- Le Yu
- Sichuan Cancer Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Ruoyi Yang
- Sichuan Cancer Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Zeng Long
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Qingxiu Tao
- Sichuan Cancer Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Bin Liu
- Sichuan Cancer Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
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14
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Hu Y, Zhou Y, Liu W, Chen M, Hao Y, Qu G, Xia Z, Zhou X, Li Y, Tan L. AXL and SHC1 confer crizotinib resistance in patient-derived xenograft model of ALK-driven lung cancer. iScience 2024; 27:110846. [PMID: 39310759 PMCID: PMC11416680 DOI: 10.1016/j.isci.2024.110846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 04/30/2024] [Accepted: 08/27/2024] [Indexed: 09/25/2024] Open
Abstract
Anaplastic lymphoma kinase (ALK) inhibitor crizotinib has dramatic effect in non-small cell lung cancer patients with ALK rearrangement. However, most patients eventually develop resistance. To discover therapeutic targets to overcome crizotinib resistance (CR), we generated patient-derived xenograft CR mice and subjected them to phosphorylation profiling, together with CR mice treated with ASP3026 or alectinib. We identified 100 proteins with different phosphorylation status in CR mice. Among them, AXL phosphorylation was increased in CR mice, which could not be reversed by ASP3026 or alectinib. Importantly, the combined treatment of crizotinib and AXL inhibitor in CR mice significantly inhibited tumor growth, compared to crizotinib alone. We also found that SHC1 phosphorylation was increased in CR mice and SHC1 knockdown sensitized ALK-driven cells to crizotinib. Our study provides a new view of signaling pathways leading to CR, suggesting AXL and SHC1 as potential targets for combination therapy to overcome CR.
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Affiliation(s)
- Yerong Hu
- Department of Cardiovascular Surgery, the Second Xiangya Hospital of Central South University, Changsha, China
| | - Yangzhao Zhou
- Department of Cardiovascular Surgery, the Second Xiangya Hospital of Central South University, Changsha, China
| | - Wenliang Liu
- Department of General Thoracic Surgery, the Second Xiangya Hospital of Central South University, Changsha, China
| | - Mingjiu Chen
- Department of General Thoracic Surgery, the Second Xiangya Hospital of Central South University, Changsha, China
| | - Yimei Hao
- Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), Shanghai, China
| | - Guojun Qu
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenkun Xia
- Department of General Thoracic Surgery, the Second Xiangya Hospital of Central South University, Changsha, China
| | - Xinmin Zhou
- Department of Cardiovascular Surgery, the Second Xiangya Hospital of Central South University, Changsha, China
| | - Yu Li
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ling Tan
- Department of Cardiovascular Surgery, the Second Xiangya Hospital of Central South University, Changsha, China
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15
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Chu F, Zhang W, Hu H. New findings on the incidence and management of CNS adverse reactions in ALK-positive NSCLC with lorlatinib treatment. Discov Oncol 2024; 15:444. [PMID: 39271557 PMCID: PMC11399364 DOI: 10.1007/s12672-024-01339-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 09/11/2024] [Indexed: 09/15/2024] Open
Abstract
To explore the presentation and control of CNS adverse reactions in patients with ALK-positive NSCLC treated with lorlatinib. This study includes a retrospective case report from Sir Run Run Shaw Hospital on a lorlatinib-treated patient with CNS adverse reactions and a systematic literature review of similar cases until January 2023. The report detailed a case of a 74-year-old male with Grade III CNS adverse reactions 25 days after starting lorlatinib, which were reversible with dose modification and pharmacotherapy. The review indicated a 19.39% occurrence rate of such reactions, with a 17% improvement rate post-dose adjustment. CNS adverse reactions frequently occur in ALK-positive NSCLC patients on lorlatinib, yet they are reversible with appropriate management. Research should continue to optimize treatment protocols to decrease these reactions' frequency.
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Affiliation(s)
- Fanfan Chu
- Department of Admission Preparation Center, College of Medicine, QianTang Campus of Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Wenxi Zhang
- Department of Admission Preparation Center, College of Medicine, QianTang Campus of Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hong Hu
- Department of Medical Oncology, College of Medicine, QianTang Campus of Sir Run Run Shaw Hospital, Zhejiang University, No. 368, Xiasha Road, Hangzhou, Zhejiang, China.
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Mastrantoni L, Giordano G, Vita E, Horn G, Russo J, Orlandi A, Daniele G, Giannarelli D, Tortora G, Bria E. The likelihood of being helped or harmed as a patient-centred tool to assess ALK-Inhibitors clinical impact and safety in ALK-addicted non-small cell lung cancer: A systematic review and sensitivity-analysis. Cancer Treat Res Commun 2024; 41:100842. [PMID: 39260066 DOI: 10.1016/j.ctarc.2024.100842] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 08/12/2024] [Accepted: 09/05/2024] [Indexed: 09/13/2024]
Abstract
BACKGROUND In untreated ALK-positive non-small cell lung cancer no randomized controlled trials (RCTs) are available directly comparing next-generation ALK-inhibitors. We conducted a sensitivity analysis using the likelihood of being helped or harmed (LHH). METHODS Phase III trials comparing ALK-inhibitors to crizotinib were included. Efficacy outcomes were progression-free survival (PFS), objective response rate (ORR), PFS in patients with brain metastases and intracranial ORR. Safety outcomes were grade 3-4 adverse events (AEs), dose reductions and discontinuations. RESULTS Six RCTs (1524 patients) were included. Lorlatinib and brigatinib had the lowest NNT for intracranial outcomes. Alectinib demonstrated favourable LHHs for grade 3-4 AEs, dose reductions and discontinuations. Brigatinib LHHs were low for common AEs, mainly laboratory anomalies and hypertension. Ensartinib showed mainly skin toxicity. Lorlatinib LHHs were low for specific grade 3-4 AEs, mainly metabolic alterations. CONCLUSIONS The four ALK-inhibitors exhibited favourable risk-benefit ratios. Lorlatinib showed the lowest NNT for systemic efficacy and, alongside with Brigatinib, lower NNTs for intracranial efficacy. Alectinib exhibited higher LHHs for AEs. REGISTRATION PROSPERO registration number: CRD42023389101.
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Affiliation(s)
- Luca Mastrantoni
- Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Giulia Giordano
- Department of Aging, Orthopedics and Reumatological Sciences, Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Emanuele Vita
- Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy; Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS Rome, Italy.
| | - Guido Horn
- Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Jacopo Russo
- Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Armando Orlandi
- Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy; Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS Rome, Italy.
| | - Gennaro Daniele
- UOC Phase I, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
| | - Diana Giannarelli
- Biostatistic, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
| | - Giampaolo Tortora
- Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy; Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS Rome, Italy.
| | - Emilio Bria
- Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy; Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS Rome, Italy; Medical Oncology Unit, Ospedale Isola Tiberina, Gemelli Isola, Rome, Italy.
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17
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Jin Y, Christenson ES, Zheng L, Li K. Neutrophils in pancreatic ductal adenocarcinoma: bridging preclinical insights to clinical prospects for improved therapeutic strategies. Expert Rev Clin Immunol 2024; 20:945-958. [PMID: 38690749 DOI: 10.1080/1744666x.2024.2348605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 04/24/2024] [Indexed: 05/03/2024]
Abstract
INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by a dismal five-year survival rate of less than 10%. Neutrophils are key components of the innate immune system, playing a pivotal role in the PDAC immune microenvironment. AREAS COVERED This review provides a comprehensive survey of the pivotal involvement of neutrophils in the tumorigenesis and progression of PDAC. Furthermore, it synthesizes preclinical and clinical explorations aimed at targeting neutrophils within the milieu of PDAC, subsequently proposing a conceptual framework to propel further inquiry focused on enhancing the therapeutic efficacy of PDAC through neutrophil-targeted strategies. PubMed and Web of Science databases were utilized for researching neutrophils in pancreatic cancer publications prior to 2024. EXPERT OPINION Neutrophils play roles in promoting tumor growth and metastasis in PDAC and are associated with poor prognosis. However, the heterogeneity and plasticity of neutrophils and their complex relationships with other immune cells and extracellular matrix also provide new insights for immunotherapy targeting neutrophils to achieve a better prognosis for PDAC.
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Affiliation(s)
- Yi Jin
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Eric S Christenson
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Lei Zheng
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Keyu Li
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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18
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Wilson I, Qiu M, Itchins M, Wang B, Huang M, Grimison P. Metastatic Non-Myofibroblastic Sarcoma Harbouring EML4-ALK Fusion-Dramatic Response to ALK Tyrosine Kinase Inhibitors and Development of Resistance Mutations. Cancer Rep (Hoboken) 2024; 7:e2164. [PMID: 39188081 PMCID: PMC11347748 DOI: 10.1002/cnr2.2164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 07/14/2024] [Accepted: 07/30/2024] [Indexed: 08/28/2024] Open
Abstract
BACKGROUND Anaplastic lymphoma kinase (ALK) rearrangements are rare in non-myofibroblastic sarcoma and there is limited data on the efficacy of ALK tyrosine kinase inhibitors (TKIs) and mechanisms of resistance in these patients. CASE A 58 year-old man with metastatic non-myofibroblastic sarcoma was found to have an EML4-ALK fusion on molecular sequencing. After progression on first line systemic therapy with doxorubicin, the patient received alectinib, a second generation ALK inhibitor, and had a marked clinical and radiological response. He progressed after 5 months of treatment. Repeat lung biopsy identified the emergence of an ALK I1171N resistance mutation. He was then treated with lorlatinib, again with rapid clinical improvement and significant partial radiological response. He progressed after 4 months, at which time a repeat lung biopsy identified a new ALK kinase domain mutation G1202R. The patient was subsequently treated with chemotherapy, though unfortunately died shortly after due to rapidly progressive disease. CONCLUSION This case report adds to a body of evidence demonstrating the potential transformative response to targeted therapy in non-lung solid organ tumours harbouring ALK fusions. This is the first description tracking the development of resistance mutations in a patient with non-myofibroblastic sarcoma and questions the utility of the presence of G1202R mutation as a marker of lorlatinib sensitivity in non-lung ALK rearranged tumours, contrary to experience in lung cancer.
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Affiliation(s)
- Isabella Wilson
- Department of Medical OncologyChris O'Brien LifehouseSydneyAustralia
- Faculty of Medicine and HealthThe University of SydneySydneyAustralia
| | - Min Qiu
- Sydpath, St Vincent's HospitalSydneyAustralia
- St Vincent's Clinical SchoolUniversity of New South WalesSydneyAustralia
| | - Malinda Itchins
- Department of Medical OncologyChris O'Brien LifehouseSydneyAustralia
- Faculty of Medicine and HealthThe University of SydneySydneyAustralia
- Department of Medical OncologyRoyal North Shore HospitalSydneyAustralia
| | - Bin Wang
- Sydpath, St Vincent's HospitalSydneyAustralia
| | - Min Li Huang
- Sydpath, St Vincent's HospitalSydneyAustralia
- Kinghorn Centre for Cancer Genomics Medicine, Garvan Institute of Medical ResearchSydneyAustralia
| | - Peter Grimison
- Department of Medical OncologyChris O'Brien LifehouseSydneyAustralia
- Faculty of Medicine and HealthThe University of SydneySydneyAustralia
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19
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John A, Vick J, Sarker S, Middleton E, Cartwright E, Manickavasagar T, McMahon D, Tokaca N, Popat S. Successful Lorlatinib Rechallenge After Severe Drug-Induced Psychosis in ALK-Positive Metastatic NSCLC: A Case Report. JTO Clin Res Rep 2024; 5:100689. [PMID: 39091593 PMCID: PMC11293564 DOI: 10.1016/j.jtocrr.2024.100689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/04/2024] Open
Abstract
Neurocognitive adverse events (NAEs) have been reported in up to 60% of patients on lorlatinib, a potent central nervous system-active ALK inhibitor. Manifestations may include psychotic, mood, speech, and cognitive symptoms. Current guidance recommends permanent discontinuation of lorlatinib in cases of grade IV NAEs. Here, we report a case of successful rechallenge of dose-reduced lorlatinib after recovery of grade IV psychosis in a patient with ALK-positive NSCLC.
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Affiliation(s)
- Alexius John
- Royal Marsden Hospital, Lung Unit, London, United Kingdom
| | - Joanna Vick
- Royal Marsden Hospital, Lung Unit, London, United Kingdom
| | - Sarah Sarker
- Royal Marsden Hospital, Lung Unit, London, United Kingdom
| | | | | | | | - David McMahon
- Royal Marsden Hospital, Lung Unit, London, United Kingdom
| | - Nadza Tokaca
- Royal Marsden Hospital, Lung Unit, London, United Kingdom
| | - Sanjay Popat
- Royal Marsden Hospital, Lung Unit, London, United Kingdom
- Institute of Cancer Research, London, United Kingdom
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20
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Xiong J, Xia L. Case report: Precise NGS and combined bevacizumab promote durable response in ALK-positive lung adenocarcinoma with multiple-line ALK-TKI resistance. Front Oncol 2024; 14:1419306. [PMID: 38978737 PMCID: PMC11228237 DOI: 10.3389/fonc.2024.1419306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 06/07/2024] [Indexed: 07/10/2024] Open
Abstract
Liquid biopsies including pleural fluid or plasma are commonly applied for patients with advanced non-small cell lung cancer (NSCLC) and pleural effusion (PE) to guide the treatment. ALK-TKIs are the first options for patients with ALK-positive mutations and combining ALK-TKIs with angiogenic agents may improve survival. We report here one case with ALK-positive lung adenocarcinoma in which the patient achieved a prolonged progression-free survival (PFS) of 97 months after undergoing precise pleural effusion NGS and receiving combined bevacizumab treatment following multiple-line ALK-TKI resistance.
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Affiliation(s)
- Jin Xiong
- Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lei Xia
- Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
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21
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Li H, Wang C, Guo C. Post-marketing safety of lorlatinib: a real-world study based on the FDA adverse event reporting system. Front Pharmacol 2024; 15:1385036. [PMID: 38903993 PMCID: PMC11188337 DOI: 10.3389/fphar.2024.1385036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 05/21/2024] [Indexed: 06/22/2024] Open
Abstract
Background Lorlatinib displays marked systemic and intracranial efficacy against anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC). We aimed to establish the safety profile of lorlatinib based on the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods Reports from the FAERS between 2019 and 2023 were collected to conduct the disproportionality analysis. Reporting odds ratio (ROR) was employed to detect the potential adverse events (AEs) related to lorlatinib. The clinical characteristics, age and gender differences, time to onset of AEs were also investigated. Results A total of 2,941 AE reports were found to be associated with lorlatinib among the 8,818,870 AE reports obtained from the FAERS database. 167 lorlatinib-related AE signals were identified. The frequently reported AEs including hypercholesterolemia, oedema, and cognitive disorder were in line with those observed in clinical trials and drug instruction. However, AEs such as interstitial lung disease and AV block indicated in the drug label require further evaluation. More attention should be paid to the new potential unexpected AEs including pulmonary arterial hypertension and radiation necrosis. Furthermore, we examined the specific high-risk AEs of different ages and genders. In addition, majority of AEs occurred within the first 2 months after lorlatinib initiation with a median onset time of 51 days. Conclusion Our study provides valuable insight into the post-marketing safety profile of lorlatinib, which can potentially benefit the rational and safe administration of lorlatinib in the clinic. Further prospective studies are needed to validate the associations between lorlatinib and the identified AEs.
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Affiliation(s)
- Huqun Li
- Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chongshu Wang
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cuilian Guo
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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22
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Shi Y, Hu X, Li X, Gong C, Wang K, Li Y, Zhang S, Luo Y, Wang P, Jiang L, Meng X, Dong X, Wang H, Yang R, Mei Q, Liu B, Yang L, Sun Y. Ficonalkib (SY-3505) in Advanced ALK-Positive NSCLC: A Multicenter, Open-Label, Single-Arm, Phase 1/2 Study. J Thorac Oncol 2024; 19:898-911. [PMID: 38295954 DOI: 10.1016/j.jtho.2024.01.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 01/22/2024] [Accepted: 01/24/2024] [Indexed: 02/23/2024]
Abstract
INTRODUCTION Treatment options for second-generation (2nd-gen) ALK tyrosine kinase inhibitor (TKI)-resistant patients are limited. We evaluated the safety, pharmacokinetics, and efficacy of ficonalkib (SY-3505), a third-generation (3rd-gen) ALK TKI, in patients with advanced ALK-positive non-small cell lung cancer. METHODS This first-in-human, phase 1/2 study (Chinese Clinical Trial Registry identifier: ChiCTR1900025619; ClinicalTrials.gov identifier: NCT05257512) had two parts. Phase 1 included a dose-escalation phase (25-800 mg quaque die [QD]) and a dose-expansion phase (500 mg QD or 600 mg QD). Phase 2 enrolled patients treated at recommended phase 2 dose. Primary end points were safety in phase 1 and objective response rate (ORR) in phase 2. RESULTS Between April 21, 2020, and August 31, 2023, a total of 127 patients with advanced ALK-positive non-small cell lung cancer were enrolled, with 62 in phase 1. Ficonalkib was well absorbed and tolerated, with one dose-limited toxicity event occurring at 800 mg QD. Treatment-related adverse events occurred in 85.5% of patients, with 19.4% experienced greater than or equal to grade 3 events. The ORR was 38.3% (23 of 60, 95% confidence interval [CI]: 26.1%-51.8%) in phase 1, and 600 mg QD was established as recommended phase 2 dose. In phase 2, a total of 65 patients received ficonalkib at 600 mg QD. In total, 88 patients received ficonalkib at 600 mg QD in phase 1/2, and all had received prior 2nd-gen ALK TKI treatment. Furthermore, 90.9% of the patients experienced treatment-related adverse events and 14.8% experienced greater than or equal to grade 3 events. The ORR in efficacy-assessable patients who received ficonalkib at 600 mg QD was 47.5% (38 of 80, 95% CI: 36.2%-59.0%), with an intracranial ORR of 37.5% (12 of 32, 95% CI: 21.1%-56.3%) in these patients with measurable brain lesions at baseline. CONCLUSIONS Ficonalkib (SY-3505) was well tolerated, with favorable safety profiles and promising efficacy in patients resistant to prior 2nd-gen ALK TKI.
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Affiliation(s)
- Yuankai Shi
- Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, the People's Republic of China.
| | - Xingsheng Hu
- Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, the People's Republic of China
| | - Xingya Li
- Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, the People's Republic of China
| | - Caifeng Gong
- Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, the People's Republic of China
| | - Ke Wang
- Department of Respiratory Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, the People's Republic of China
| | - Yongsheng Li
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, the People's Republic of China
| | - Shucai Zhang
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, the People's Republic of China
| | - Yongzhong Luo
- Thoracic Medicine Department 1, Hunan Cancer Hospital, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, the People's Republic of China
| | - Pingli Wang
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, the People's Republic of China
| | - Liyan Jiang
- Department of Respiratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, the People's Republic of China
| | - Xiangjiao Meng
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, the People's Republic of China
| | - Xiaorong Dong
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, the People's Republic of China
| | - Huijuan Wang
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, the People's Republic of China
| | - Runxiang Yang
- Department of Medical Oncology, Yunnan Cancer Hospital, Kunming Medical University, Kunming, Yunnan, the People's Republic of China
| | - Qi Mei
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, the People's Republic of China
| | - Baogang Liu
- Department of Respiratory Medicine, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, the People's Republic of China
| | - Limin Yang
- Shouyao Holdings (Beijing) Co.,Ltd., Beijing, the People's Republic of China
| | - Yinghui Sun
- Shouyao Holdings (Beijing) Co.,Ltd., Beijing, the People's Republic of China
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Ren X, Zhang X, Lei X, Ma W, Zhang T, Wang Y, Ren J. Comparison of clinical and MRI features of brain metastases between ALK+ and ALK- NSCLC. Cancer Med 2024; 13:e7405. [PMID: 38881327 PMCID: PMC11180969 DOI: 10.1002/cam4.7405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/21/2024] [Accepted: 06/07/2024] [Indexed: 06/18/2024] Open
Abstract
BACKGROUND Non-small-cell lung cancer (NSCLC) is the primary cause of brain metastases (BM). This study aimed to investigate differences in clinical and magnetic resonance imaging (MRI) features of BM between anaplastic lymphoma kinase (ALK) gene fusion (ALK+) and ALK wild-type (ALK-) NSCLC, and to preliminarily assess the efficacy of radiotherapy for treating BM. METHODS A retrospective analysis included 101 epidermal growth factor receptor (EGFR)- NSCLC patients with BM: 41 with ALK gene fusion and 60 being ALK-. The brain MRI and clinical features were compared between different ALK status using the multivariate analysis, and a nomogram was constructed to predict ALK gene fusion. Fifty-six patients who did not undergo cerebral surgery and had complete pre- and post- treatment data were further divided based on whether they received radiotherapy. Log-rank test was used to compare the short-term effect of treatment between the two groups under different genotypes. RESULTS ALK+ BM exhibited decreased peritumoral brain edema size, lower peritumoral brain edema index (PBEI), and a more homogeneous contrast enhancement pattern compared to ALK- BM. Age (OR = 1.04; 95%CI: 1.02-1.06), time to BM (OR = 1.50; 95% CI: 1.04-2.14), PBEI (OR = 1.26; 95% CI: 0.97-1.62), smoking status (smoking index >400 vs. non-smoking status: OR = 1.42; 95% CI: 0.99-2.04) and contrast enhancement pattern (OR = 1.89; 95% CI: 1.28-2.78) were associated with ALK gene fusion. A nomogram based on these variables demonstrated acceptable predictive efficiency (AUC = 0.844). In the ALK+ group, patients who received radiotherapy did not show increased disease control rate (DCR) or progression-free survival (PFS). In contrast, in the ALK- group, those who received radiotherapy had improved objective response rate (ORR), DCR, and PFS compared to those who were only treated with systemic therapy. CONCLUSIONS The clinical and MRI features of BM can indicate the status of ALK in NSCLC. In the ALK- group, patients who received radiotherapy showed higher ORR, DCR, and PFS compared to those who did not.
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Affiliation(s)
- Xiaolu Ren
- Department of RadiotherapyShanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical UniversityTaiyuanShanxiChina
| | - Xuting Zhang
- Department of RadiologyShanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical UniversityTaiyuanShanxiChina
| | - Xiaoyan Lei
- Institute of Medical ImagingShanxi Medical UniversityTaiyuanShanxiChina
| | - Weiqin Ma
- Institute of Medical ImagingShanxi Medical UniversityTaiyuanShanxiChina
| | - Ting Zhang
- Department of RadiologyShanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical UniversityTaiyuanShanxiChina
| | - Yuxiang Wang
- Department of UltrasoundShanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical UniversityTaiyuanShanxiChina
| | - Jiwei Ren
- Department of RadiologyShanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical UniversityTaiyuanShanxiChina
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Gemelli M, Albini A, Catalano G, Incarbone M, Cannone M, Balladore E, Ricotta R, Pelosi G. Navigating resistance to ALK inhibitors in the lorlatinib era: a comprehensive perspective on NSCLC. Expert Rev Anticancer Ther 2024; 24:347-361. [PMID: 38630549 DOI: 10.1080/14737140.2024.2344648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 04/15/2024] [Indexed: 04/19/2024]
Abstract
INTRODUCTION The emergence of anaplastic lymphoma kinase (ALK) rearrangements in non-small cell lung cancer (NSCLC) has revolutionized targeted therapy. This dynamic landscape, featuring novel ALK inhibitors and combination therapies, necessitates a profound understanding of resistance mechanisms for effective treatment strategies. Recognizing two primary categories - on-target and off-target resistance - underscores the need for comprehensive assessment. AREAS COVERED This review delves into the intricacies of resistance to ALK inhibitors, exploring complexities in identification and management. Molecular testing, pivotal for early detection and accurate diagnosis, forms the foundation for patient stratification and resistance management. The literature search methodology involved comprehensive exploration of Pubmed and Embase. The multifaceted perspective encompasses new therapeutic horizons, ongoing clinical trials, and their clinical implications post the recent approval of lorlatinib. EXPERT OPINION Our expert opinion encapsulates the critical importance of understanding resistance mechanisms in the context of ALK inhibitors for shaping successful treatment approaches. With a focus on molecular testing and comprehensive assessment, this review contributes valuable insights to the evolving landscape of NSCLC therapy.
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Affiliation(s)
- Maria Gemelli
- Medical Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Adriana Albini
- Departement of Scientific Directorate, European Institute of Oncology (IEO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
| | - Gianpiero Catalano
- Radiation Oncology Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Matteo Incarbone
- Department of Surgery, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Maria Cannone
- Inter-Hospital Division of Pathology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Emanuela Balladore
- Inter-Hospital Division of Pathology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Riccardo Ricotta
- Medical Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Giuseppe Pelosi
- Inter-Hospital Division of Pathology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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Romiani A, Simonsson K, Pettersson D, Al-Awar A, Rassol N, Bakr H, Lind D, Umapathy G, Spetz J, Palmer R, Hallberg B, Helou K, Forssell-Aronsson E. Comparison of 177Lu-octreotate and 177Lu-octreotide for treatment in human neuroblastoma-bearing mice. Heliyon 2024; 10:e31409. [PMID: 38826727 PMCID: PMC11141386 DOI: 10.1016/j.heliyon.2024.e31409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 05/01/2024] [Accepted: 05/15/2024] [Indexed: 06/04/2024] Open
Abstract
Background Patients with high-risk neuroblastoma (NB) have a 5-year event-free survival of less than 50 %, and novel and improved treatment options are needed. Radiolabeled somatostatin analogs (SSTAs) could be a treatment option. The aims of this work were to compare the biodistribution and the therapeutic effects of 177Lu-octreotate and 177Lu-octreotide in mice bearing the human CLB-BAR NB cell line, and to evaluate their regulatory effects on apoptosis-related genes. Methods The biodistribution of 177Lu-octreotide in mice bearing CLB-BAR tumors was studied at 1, 24, and 168 h after administration, and the absorbed dose was estimated to tumor and normal tissues. Further, animals were administered different amounts of 177Lu-octreotate or 177Lu-octreotide. Tumor volume was measured over time and compared to a control group given saline. RNA was extracted from tumors, and the expression of 84 selected genes involved in apoptosis was quantified with qPCR. Results The activity concentration was generally lower in most tissues for 177Lu-octreotide compared to 177Lu-octreotate. Mean absorbed dose per administered activity to tumor after injection of 1.5 MBq and 15 MBq was 0.74 and 0.03 Gy/MBq for 177Lu-octreotide and 2.9 and 0.45 Gy/MBq for 177Lu-octreotate, respectively. 177Lu-octreotide treatment resulted in statistically significant differences compared to controls. Fractionated administration led to a higher survival fraction than after a single administration. The pro-apoptotic genes TNSFS8, TNSFS10, and TRADD were regulated after administration with 177Lu-octreotate. Treatment with 177Lu-octreotide yielded regulation of the pro-apoptotic genes CASP5 and TRADD, and of the anti-apoptotic gene IL10 as well as the apoptosis-related gene TNF. Conclusion 177Lu-octreotide gave somewhat better anti-tumor effects than 177Lu-octreotate. The similar effect observed in the treated groups with 177Lu-octreotate suggests saturation of the somatostatin receptors. Pronounced anti-tumor effects following fractionated administration merited receptor saturation as an explanation. The gene expression analyses suggest apoptosis activation through the extrinsic pathway for both radiopharmaceuticals.
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Affiliation(s)
- A. Romiani
- Department of Medical Radiation Sciences, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - K. Simonsson
- Department of Medical Radiation Sciences, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - D. Pettersson
- Department of Medical Radiation Sciences, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - A. Al-Awar
- Department of Medical Radiation Sciences, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - N. Rassol
- Department of Medical Radiation Sciences, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - H. Bakr
- Department of Medical Radiation Sciences, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Medical Physics and Biomedical Engineering, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - D.E. Lind
- Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - G. Umapathy
- Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - J. Spetz
- Department of Medical Radiation Sciences, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - R.H. Palmer
- Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - B. Hallberg
- Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - K. Helou
- Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - E. Forssell-Aronsson
- Department of Medical Radiation Sciences, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Medical Physics and Biomedical Engineering, Sahlgrenska University Hospital, Gothenburg, Sweden
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Poei D, Ali S, Ye S, Hsu R. ALK inhibitors in cancer: mechanisms of resistance and therapeutic management strategies. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2024; 7:20. [PMID: 38835344 PMCID: PMC11149099 DOI: 10.20517/cdr.2024.25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/18/2024] [Accepted: 05/08/2024] [Indexed: 06/06/2024]
Abstract
Anaplastic lymphoma kinase (ALK) gene rearrangements have been identified as potent oncogenic drivers in several malignancies, including non-small cell lung cancer (NSCLC). The discovery of ALK inhibition using a tyrosine kinase inhibitor (TKI) has dramatically improved the outcomes of patients with ALK-mutated NSCLC. However, the emergence of intrinsic and acquired resistance inevitably occurs with ALK TKI use. This review describes the molecular mechanisms of ALK TKI resistance and discusses management strategies to overcome therapeutic resistance.
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Affiliation(s)
- Darin Poei
- Department of Internal Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Sana Ali
- Division of Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
| | - Shirley Ye
- Department of Internal Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Robert Hsu
- Division of Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
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Kumar A, Kapoor A, Noronha V, Patil V, Menon N, Singh AK, Joshi A, Janu A, Kaushal RK, Pai T, Chougule A, Shetty O, Prabhash K. Lorlatinib in the second line and beyond for ALK positive lung cancer: real-world data from resource-constrained settings. BJC REPORTS 2024; 2:35. [PMID: 39516655 PMCID: PMC11523971 DOI: 10.1038/s44276-024-00055-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 02/27/2024] [Accepted: 03/06/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND ALK-positive lung cancers are known to have favorable responses with oral tyrosine kinase inhibitors. Lorlatinib is an approved treatment option post first and second-line ALK inhibitors and is now also in first line. We present a retrospective observational study of the safety and efficacy of patients receiving Lorlatinib in second-line and beyond. METHODS We conducted a retrospective observational study of ALK-positive patients who received Lorlatinib post-progression or intolerance to initial therapy at the Medical Oncology department. The patients who were started on Lorlatinib between January 2018 to December 2019 were included. The patients underwent routine blood and radiological evaluation every two to three months. RESULTS A total of 38 patients received Lorlatinib in the specified period. The median age was 48 years (range 23-68), with 53% of patients being male, 37% having comorbidities; the most common being hypertension and diabetes and 79% of patients were of ECOG-PS1. Twenty-two patients (58%) had received two prior TKIs. The most common sites of metastasis before starting Lorlatinib were brain (55%) and bone (53%). All patients except one received prior whole-brain radiotherapy with 4 receiving radiation twice. The median follow-up period was 49 months (95% CI: 46.4-51.6). Eighty-four percent showed disease control with median progression-free survival (PFS) and overall survival (OS) of 16 months (95% CI 5.4-26.6) and 22 months (95% CI 9.9-34.1) respectively. Twelve patients died without documented progression. Five out of twelve with documented progression had brain involvement while six had lung involvement. Twelve out of twenty-four patients who progressed received subsequent chemotherapy. The most common grade 3 and above toxicities were hypercholesterolemia and hypertriglyceridemia. Three (7.8%) patients required dose reduction. CONCLUSION This real-world data confirms the efficacy of Lorlatinib in the second line and beyond with adverse effects matching that of registration studies.
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Affiliation(s)
- Amit Kumar
- Department of Medical Oncology, Homi Bhabha Cancer Hospital and Research Centre(A Unit of Tata Memorial Centre, Mumbai), Muzaffarpur-, 842001, Bihar, India
| | - Akhil Kapoor
- Department of Medical Oncology, Mahamana Pandit Madan Mohan Malviya Cancer Center and Homi Bhabha Cancer Hospital (A Unit of Tata Memorial Centre, Mumbai), Varanasi, 221005, Uttar Pradesh, India
| | - Vanita Noronha
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India
| | - Vijay Patil
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India
| | - Nandini Menon
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India
| | - Ajay Kumar Singh
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India
| | - Amit Joshi
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India
| | - Amit Janu
- Department of Radiology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India
| | - Rajiv Kumar Kaushal
- Department of Pathology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India
| | - Trupti Pai
- Department of Pathology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India
| | - Anuradha Chougule
- Department of Molecular Pathology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India
| | - Omshree Shetty
- Department of Molecular Pathology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India
| | - Kumar Prabhash
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India.
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Liu G, Mazieres J, Stratmann J, Ou SHI, Mok T, Grizzard M, Goto Y, Felip E, Solomon BJ, Bauer TM. A pragmatic guide for management of adverse events associated with lorlatinib. Lung Cancer 2024; 191:107535. [PMID: 38554546 DOI: 10.1016/j.lungcan.2024.107535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 03/07/2024] [Accepted: 03/11/2024] [Indexed: 04/01/2024]
Abstract
Lorlatinib is a brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) indicated for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). In clinical trials, lorlatinib has shown durable efficacy and a manageable safety profile in treatment-naive patients and in those who have experienced progression while receiving first- and/or second-generation ALK TKIs. Lorlatinib has a distinct safety profile from other ALK TKIs, including hyperlipidemia and central nervous system effects. Clinical trial data showed that most adverse events (AEs) can be managed effectively or reversed with dose modifications (such as dose interruptions or reductions) or with concomitant medications without compromising clinical efficacy or quality of life for patients. A pragmatic approach to managing AEs related to lorlatinib is required. We present patient-focused recommendations for the evaluation and management of select AEs associated with lorlatinib developed by clinicians and nurses with extensive lorlatinib expertise in routine clinical practice. The recommendations follow the general framework of "prepare, monitor, manage, reassess" to streamline AE management and assist in practical, actionable, and personalized patient care.
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Affiliation(s)
- Geoffrey Liu
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
| | - Julien Mazieres
- Thoracic Oncology Department, Toulouse University Hospital, Toulouse, France.
| | - Jan Stratmann
- Department of Medicine II, Hematology/Oncology, University Hospital Frankfurt, Frankfurt, and National Network Genomic Medicine Lung Cancer, Cologne, Germany.
| | - Sai-Hong Ignatius Ou
- Chao Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA, USA.
| | - Tony Mok
- State Key Laboratory of South China, Chinese University of Hong Kong, Hong Kong Special Administrative Region of China, China.
| | - Mary Grizzard
- Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA.
| | - Yasushi Goto
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
| | - Enriqueta Felip
- Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
| | | | - Todd M Bauer
- Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA.
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Villa M, Malighetti F, Sala E, Sharma GG, Arosio G, Gemelli M, Manfroni C, Fontana D, Cordani N, Meneveri R, Zambon A, Piazza R, Pagni F, Cortinovis D, Mologni L. New pan-ALK inhibitor-resistant EML4::ALK mutations detected by liquid biopsy in lung cancer patients. NPJ Precis Oncol 2024; 8:29. [PMID: 38448512 PMCID: PMC10918084 DOI: 10.1038/s41698-024-00498-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 12/21/2023] [Indexed: 03/08/2024] Open
Abstract
ALK and ROS1 fusions are effectively targeted by tyrosine kinase inhibitors (TKIs), however patients inevitably relapse after an initial response, often due to kinase domain mutations. We investigated circulating DNA from TKI-relapsed NSCLC patients by deep-sequencing. New EML4::ALK substitutions, L1198R, C1237Y and L1196P, were identified in the plasma of NSCLC ALK patients and characterized in a Ba/F3 cell model. Variants C1237Y and L1196P demonstrated pan-inhibitor resistance across 5 clinical and 2 investigational TKIs.
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Affiliation(s)
- Matteo Villa
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Federica Malighetti
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Elisa Sala
- SC Medical Oncology, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Geeta G Sharma
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Giulia Arosio
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Maria Gemelli
- SC Medical Oncology, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
- Medical Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Chiara Manfroni
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Diletta Fontana
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Nicoletta Cordani
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Raffaella Meneveri
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Alfonso Zambon
- Department of Chemistry and Geological Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Rocco Piazza
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Fabio Pagni
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- Department of Pathology, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Diego Cortinovis
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- SC Medical Oncology, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Luca Mologni
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
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30
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Mayer-Suess L, Knoflach M, Pircher A, Kiechl S, Schmidauer C, Hametner E. Case report: Dissolving carotid plaque associated to Lorlatinib-related dyslipidemia. Front Oncol 2024; 14:1322501. [PMID: 38505589 PMCID: PMC10949858 DOI: 10.3389/fonc.2024.1322501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 02/19/2024] [Indexed: 03/21/2024] Open
Abstract
We present a case with prolonged Lorlatinib-related dyslipidemia causing internal carotid artery stenosis, putting the patient at risk of cerebrovascular events. Through intensified lipid-lowering treatment and dose reduction of Lorlatinib, LDL-C levels decreased markedly. Surprisingly, the left sided internal carotid artery stenosis dissolved accordingly. Due to the high efficacy of the new selective tyrosine kinase inhibitors and resulting long-term treatment, it is essential to carefully follow-up and include drug specific side effect monitoring. This case emphasizes that Loraltinib-related dyslipidemia has to be taken seriously and treatment should be initiated as promptly as possible. We conclude that in cases were lipid dysregulation remains and Lorlatinib treatment has to be continued, cerebrovascular appraisal through ultrasound should be considered and, if stenosis is evident, intensified treatment regimen of dyslipidemia or dose reduction of Lorlatinib should be discussed in an interdisciplinary setting.
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Affiliation(s)
- Lukas Mayer-Suess
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Michael Knoflach
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
- VASCage, Centre on Clinical Stroke Research, Innsbruck, Austria
| | - Andreas Pircher
- Department of Internal Medicine V, Hematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan Kiechl
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
- VASCage, Centre on Clinical Stroke Research, Innsbruck, Austria
| | | | - Eva Hametner
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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Schoenmaekers J, Dijkstra J, van der Wekken A, Paats M, Broen M, Brandts L, Dingemans AM, Hendriks L. In-depth Analysis of Lorlatinib-related neurocognitive Adverse Events in Patients With Non-small-cell Lung Cancer. Clin Lung Cancer 2024; 25:168-174.e1. [PMID: 38151408 DOI: 10.1016/j.cllc.2023.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 11/29/2023] [Accepted: 12/09/2023] [Indexed: 12/29/2023]
Abstract
INTRODUCTION Lorlatinib is a potent, brain penetrant, next-generation ALK/ROS1 TKI, with high response rates and durable responses, including the brain. However, a significant drawback is the manifestation of neurocognitive adverse events (NCAEs). Despite being generally low-grade in severity, these NCAEs can be physically and mentally disabling. Extensive neurocognitive testing in this group of patients is lacking; therefore we conducted this study. PATIENTS AND METHODS This observational prospective study was conducted across 3 Dutch university hospitals. Patients with metastatic NSCLC with an ALK- or ROS1-rearrangement and having an indication to start lorlatinib in daily clinical practice were eligible. The primary endpoints were to identify changes in neurocognitive functioning, measured through neurocognitive assessment at intervals of 2 weeks and 2 months after starting lorlatinib, in comparison to baseline. As a secondary endpoint, the correlation between neurocognitive impairment and self-reported neurocognitive dysfunction was examined. RESULTS Between June 2019 and October 2022, 22 patients were included. Among the various neurocognitive tests administered, only the Hopkins Verbal Learning Test-Revised parts b and c demonstrated a significant and clinically relevant decrease in scoring 2 weeks post initiation of lorlatinib (P = .036 and P = .003, respectively). However, these returned to baseline at the 2-month evaluation. The questionnaires did not result in significantly different outcomes over time. CONCLUSION Lorlatinib treatment did not result in a sustained and significant decline within any of the specified neurocognitive domains.
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Affiliation(s)
- Janna Schoenmaekers
- Department of Pulmonary Diseases, GROW - School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Jeanet Dijkstra
- Department of Medical Psychology, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Anthonie van der Wekken
- Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Marthe Paats
- Department Pulmonary Diseases, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands
| | - Martijn Broen
- Department of Neurology, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Lloyd Brandts
- Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Center +, Maastricht, the Netherlands
| | - Anne-Marie Dingemans
- Department Pulmonary Diseases, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands
| | - Lizza Hendriks
- Department of Pulmonary Diseases, GROW - School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, the Netherlands.
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Friedlaender A, Perol M, Banna GL, Parikh K, Addeo A. Oncogenic alterations in advanced NSCLC: a molecular super-highway. Biomark Res 2024; 12:24. [PMID: 38347643 PMCID: PMC10863183 DOI: 10.1186/s40364-024-00566-0] [Citation(s) in RCA: 39] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 01/17/2024] [Indexed: 02/15/2024] Open
Abstract
Lung cancer ranks among the most common cancers world-wide and is the first cancer-related cause of death. The classification of lung cancer has evolved tremendously over the past two decades. Today, non-small cell lung cancer (NSCLC), particularly lung adenocarcinoma, comprises a multitude of molecular oncogenic subsets that change both the prognosis and management of disease.Since the first targeted oncogenic alteration identified in 2004, with the epidermal growth factor receptor (EGFR), there has been unprecedented progress in identifying and targeting new molecular alterations. Almost two decades of experience have allowed scientists to elucidate the biological function of oncogenic drivers and understand and often overcome the molecular basis of acquired resistance mechanisms. Today, targetable molecular alterations are identified in approximately 60% of lung adenocarcinoma patients in Western populations and 80% among Asian populations. Oncogenic drivers are largely enriched among non-smokers, east Asians, and younger patients, though each alteration has its own patient phenotype.The current landscape of druggable molecular targets includes EGFR, anaplastic lymphoma kinase (ALK), v-raf murine sarcoma viral oncogene homolog B (BRAF), ROS proto-oncogene 1 (ROS1), Kirstin rat sarcoma virus (KRAS), human epidermal receptor 2 (HER2), c-MET proto-oncogene (MET), neurotrophic receptor tyrosine kinase (NTRK), rearranged during transfection (RET), neuregulin 1 (NRG1). In addition to these known targets, others including Phosphoinositide 3-kinases (PI3K) and fibroblast growth factor receptor (FGFR) have garnered significant attention and are the subject of numerous ongoing trials.In this era of personalized, precision medicine, it is of paramount importance to identify known or potential oncogenic drivers in each patient. The development of targeted therapy is mirrored by diagnostic progress. Next generation sequencing offers high-throughput, speed and breadth to identify molecular alterations in entire genomes or targeted regions of DNA or RNA. It is the basis for the identification of the majority of current druggable alterations and offers a unique window into novel alterations, and de novo and acquired resistance mechanisms.In this review, we discuss the diagnostic approach in advanced NSCLC, focusing on current oncogenic driver alterations, through their pathophysiology, management, and future perspectives. We also explore the shortcomings and hurdles encountered in this rapidly evolving field.
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Affiliation(s)
- Alex Friedlaender
- Clinique Générale Beaulieu, Geneva, Switzerland
- Oncology Department, University Hospital Geneva, Rue Gentil Perret 4. 1205, Geneva, Switzerland
| | - Maurice Perol
- Department of Medical Oncology, Centre Léon Bérard, Lyon, France
| | - Giuseppe Luigi Banna
- Portsmouth Hospitals University NHS Trust, Portsmouth, UK
- Faculty of Science and Health, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK
| | | | - Alfredo Addeo
- Oncology Department, University Hospital Geneva, Rue Gentil Perret 4. 1205, Geneva, Switzerland.
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Mousa DPV, Mavrovounis G, Argyropoulos D, Stranjalis G, Kalamatianos T. Anaplastic Lymphoma Kinase (ALK) in Posterior Cranial Fossa Tumors: A Scoping Review of Diagnostic, Prognostic, and Therapeutic Perspectives. Cancers (Basel) 2024; 16:650. [PMID: 38339401 PMCID: PMC10854950 DOI: 10.3390/cancers16030650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 01/25/2024] [Accepted: 01/29/2024] [Indexed: 02/12/2024] Open
Abstract
Anaplastic Lymphoma Kinase (ALK) has been implicated in several human cancers. This review aims at mapping the available literature on the involvement of ALK in non-glial tumors localized in the posterior cranial fossa and at identifying diagnostic, prognostic, and therapeutic considerations. Following the PRISMA-ScR guidelines, studies were included if they investigated ALK's role in primary CNS, non-glial tumors located in the posterior cranial fossa. A total of 210 manuscripts were selected for full-text review and 16 finally met the inclusion criteria. The review included 55 cases of primary, intracranial neoplasms with ALK genetic alterations and/or protein expression, located in the posterior fossa, comprising of medulloblastoma, anaplastic large-cell lymphoma, histiocytosis, inflammatory myofibroblastic tumors, and intracranial myxoid mesenchymal tumors. ALK pathology was investigated via immunohistochemistry or genetic analysis. Several studies provided evidence for potential diagnostic and prognostic value for ALK assessment as well as therapeutic efficacy in its targeting. The available findings on ALK in posterior fossa tumors are limited. Nevertheless, previous findings suggest that ALK assessment is of diagnostic and prognostic value in medulloblastoma (WNT-activated). Interestingly, a substantial proportion of ALK-positive/altered CNS histiocytoses thus far identified have been localized in the posterior fossa. The therapeutic potential of ALK inhibition in histiocytosis warrants further investigation.
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Affiliation(s)
| | - Georgios Mavrovounis
- Department of Neurosurgery, Faculty of Medicine, School of Health Sciences, University of Thessaly, 41334 Larissa, Greece;
- Department of Neurosurgery, Evangelismos Hospital, School of Medicine, Faculty of Health Sciences, National and Kapodistrian University of Athens, 10676 Athens, Greece;
| | - Dionysios Argyropoulos
- Department of Psychiatry, Eginition Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece;
| | - George Stranjalis
- Department of Neurosurgery, Evangelismos Hospital, School of Medicine, Faculty of Health Sciences, National and Kapodistrian University of Athens, 10676 Athens, Greece;
| | - Theodosis Kalamatianos
- Department of Neurosurgery, Evangelismos Hospital, School of Medicine, Faculty of Health Sciences, National and Kapodistrian University of Athens, 10676 Athens, Greece;
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Balasundaram A, Doss GPC. A computational examination of the therapeutic advantages of fourth-generation ALK inhibitors TPX-0131 and repotrectinib over third-generation lorlatinib for NSCLC with ALK F1174C/L/V mutations. Front Mol Biosci 2024; 10:1306046. [PMID: 38274094 PMCID: PMC10808363 DOI: 10.3389/fmolb.2023.1306046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 12/18/2023] [Indexed: 01/27/2024] Open
Abstract
Background: In non-small-cell lung cancer (NSCLC), a pivotal factor in promoting cancer development is the rearrangement in the anaplastic lymphoma kinase ALK gene, resulting in elevated ALK protein expression. F1174C/L/V is the acquired secondary resistant mutation in ALK. Significant survival improvements have been seen while tyrosine kinase inhibitors specifically target ALK. Nevertheless, the emergence of drug resistance hinders the clinical effectiveness of these drugs. Objective: This research sought to find the binding affinity/inhibitory effects of the existing drug lorlatinib (LOR) and upcoming TPX-0131 (zotizalkib/TPX) and repotrectinib (TPX-0005/REP) inhibitors against ALK F1174C/L/V mutations using computational approaches to identify potential strategies over resistance. Methods: We conducted molecular docking, molecular dynamics simulation, and MMPBSA calculations to investigate how compact macrocyclic inhibitors, such as TPX-0131 and repotrectinib, fit within the ATP-binding boundary and differ from LOR. Results: Our results demonstrated that TPX-0131 and repotrectinib contributed to higher binding energy in F1174C and F1174L mutations than LOR. Repotrectinib showed greater binding energy in the F1174V mutation, whereas LOR and TPX-0131 exhibited similar binding energy. However, all three inhibitors showed significant binding energy toward F1174C/L/V mutations found in NSCLC. Conclusion: This comparative study of the potential binding effects of fourth-generation inhibitors TPX-0131 and repotrectinib and third-generation inhibitor LOR for ALK F1174C/L/V mutations revealed the atomistic insights of the binding mechanism. These computational findings enable us to carry out further research for the clinical implementation of fourth-generation ALK inhibitors on ALK-positive NSCLC.
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Meng Y, Zhu M, Yang J, Wang X, Liang Y, Yu M, Li L, Kong F. Treatment Advances in Lung Cancer with Leptomeningeal Metastasis. Curr Cancer Drug Targets 2024; 24:910-919. [PMID: 38279718 DOI: 10.2174/0115680096276133231201061114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 10/11/2023] [Accepted: 11/16/2023] [Indexed: 01/28/2024]
Abstract
Leptomeningeal metastasis (LM) is a serious and often fatal complication in patients with advanced lung cancer, resulting in significant neurological deficits, decreased quality of life, and a poor prognosis. This article summarizes current research advances in treating lung cancer with meningeal metastases, discusses clinical challenges, and explores treatment strategies. Through an extensive review of relevant clinical trial reports and screening of recent conference abstracts, we collected clinical data on treating patients with lung cancer with meningeal metastases to provide an overview of the current research progress. Exciting progress has been made by focusing on specific mutations within lung cancer, including the use of EGFR tyrosine kinase inhibitors or inhibitors for anaplastic lymphoma kinase gene rearrangement, such as osimertinib, alectinib, and lorlatinib. These targeted therapies have shown impressive results in penetrating the central nervous system (CNS). Regarding whole-brain radiotherapy, there is currently some controversy among investigators regarding its effect on survival. Additionally, immune checkpoint inhibitors (ICIs) have demonstrated reliable clinical benefits due to their ability to retain anticancer activity in CNS metastases. Moreover, combination therapy shows promise in providing further treatment possibilities. Considerable progress has been made in the clinical research of lung cancer with LM. However, the sample size of prospective clinical trials investigating LM for lung cancer is still limited, with most reports being retrospective. Developing more effective management protocols for metastatic LM in lung cancer remains an ongoing challenge for the future.
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Affiliation(s)
- Yuan Meng
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Anshanxi Road, Nankai District, 300193, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Meiying Zhu
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Anshanxi Road, Nankai District, 300193, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Jie Yang
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Anshanxi Road, Nankai District, 300193, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Xuerui Wang
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Anshanxi Road, Nankai District, 300193, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yangyueying Liang
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Anshanxi Road, Nankai District, 300193, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Minghui Yu
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Anshanxi Road, Nankai District, 300193, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Longhui Li
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Anshanxi Road, Nankai District, 300193, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Fanming Kong
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Anshanxi Road, Nankai District, 300193, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
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Ekram J, Rathore A, Avila C, Hussein R, Alomar M. Unveiling the Cardiotoxicity Conundrum: Navigating the Seas of Tyrosine Kinase Inhibitor Therapies. Cancer Control 2024; 31:10732748241285755. [PMID: 39318033 PMCID: PMC11440564 DOI: 10.1177/10732748241285755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/26/2024] Open
Abstract
Background: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of various solid and hematologic malignancies by targeting dysregulated signaling pathways critical for malignant cell growth. However, these therapeutic benefits are often accompanied by cardiotoxicities, such as hypertension, left ventricular dysfunction, QT prolongation, and tachyarrhythmias, among others. These cardiotoxicities post a significant challenge in clinical management, often limiting the use of otherwise effective therapies. The underlying mechanism of TKI-induced cardiotoxicity appears to be multifaceted, involving several pathways including: direct cardiomyocyte damage, mitochondrial dysfunction, endothelial damage, and disruption of signaling pathways critical for cardiac function. The range and severity of cardiotoxicities vary significantly across different TKIs, necessitating a comprehensive understanding of each agent's specific cardiovascular risk profile. Preventing and managing TKI-induced cardiotoxicity requires a comprehensive, multidisciplinary approach. Early identification of at-risk patients through baseline cardiovascular risk assessments and appropriate monitoring during therapy is crucial. Strategies to mitigate cardiotoxic effects include dose modification, the use of cardioprotective agents, and temporary discontinuation of therapy. Additionally, decision making via multidisciplinary teams ensures minimization of cardiovascular complications while also continuing effective cancer treatment. Historically, data have been limited regarding cardiotoxicity and most cancer therapies, which certainly includes TKIs. This review aims to synthesize the current body of knowledge on TKI-associated cardiotoxicities, while highlighting the importance of vigilance and proactive management to minimize cardiovascular complications.
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Affiliation(s)
- Jahanzaib Ekram
- Morsani College of Medicine, University of South Florida, Tampa, FL, USA
- Department of Cardio-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Azeem Rathore
- Department of Internal Medicine, University of Florida Health Science Center, Gainesville, FL, USA
| | - Carlos Avila
- Department of Internal Medicine, Manatee Memorial Hospital, Bradenton, FL, USA
| | - Rahbia Hussein
- Department of Internal Medicine, Manatee Memorial Hospital, Bradenton, FL, USA
| | - Mohammed Alomar
- Morsani College of Medicine, University of South Florida, Tampa, FL, USA
- Department of Cardio-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
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Mesquita FP, Lima LB, da Silva EL, Souza PFN, de Moraes MEA, Burbano RMR, Montenegro RC. A Review on Anaplastic Lymphoma Kinase (ALK) Rearrangements and Mutations: Implications for Gastric Carcinogenesis and Target Therapy. Curr Protein Pept Sci 2024; 25:539-552. [PMID: 38424421 DOI: 10.2174/0113892037291318240130103348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 01/10/2024] [Accepted: 01/17/2024] [Indexed: 03/02/2024]
Abstract
Gastric adenocarcinoma is a complex disease with diverse genetic modifications, including Anaplastic Lymphoma Kinase (ALK) gene changes. The ALK gene is located on chromosome 2p23 and encodes a receptor tyrosine kinase that plays a crucial role in embryonic development and cellular differentiation. ALK alterations can result from gene fusion, mutation, amplification, or overexpression in gastric adenocarcinoma. Fusion occurs when the ALK gene fuses with another gene, resulting in a chimeric protein with constitutive kinase activity and promoting oncogenesis. ALK mutations are less common but can also result in the activation of ALK signaling pathways. Targeted therapies for ALK variations in gastric adenocarcinoma have been developed, including ALK inhibitors that have shown promising results in pre-clinical studies. Future studies are needed to elucidate the ALK role in gastric cancer and to identify predictive biomarkers to improve patient selection for targeted therapy. Overall, ALK alterations are a relevant biomarker for gastric adenocarcinoma treatment and targeted therapies for ALK may improve patients' overall survival.
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Affiliation(s)
- Felipe Pantoja Mesquita
- Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, CE, 60430-275, Brazil
| | - Luina Benevides Lima
- Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, CE, 60430-275, Brazil
| | - Emerson Lucena da Silva
- Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, CE, 60430-275, Brazil
| | - Pedro Filho Noronha Souza
- Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, CE, 60430-275, Brazil
| | | | - Rommel Mario Rodrigues Burbano
- Department of Biological Sciences, Oncology Research Center, Federal University of Pará, Belém, Brazil
- Molecular Biology Laboratory, Ophir Loyola Hospital, Belém, Brazil
| | - Raquel Carvalho Montenegro
- Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, CE, 60430-275, Brazil
- Latinoamericana de Implementación y Validación de guias clinicas Farmacogenomicas (RELIVAF), Brazil
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Kondo N, Utsumi T, Shimizu Y, Takemoto A, Oh-hara T, Uchibori K, Subat-Motoshi S, Ninomiya H, Takeuchi K, Nishio M, Miyazaki Y, Katayama R. MIG6 loss confers resistance to ALK/ROS1 inhibitors in NSCLC through EGFR activation by low-dose EGF. JCI Insight 2023; 8:e173688. [PMID: 37917191 PMCID: PMC10807714 DOI: 10.1172/jci.insight.173688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 10/31/2023] [Indexed: 11/04/2023] Open
Abstract
Although tyrosine kinase inhibitor (TKI) therapy shows marked clinical efficacy in patients with anaplastic lymphoma kinase-positive (ALK+) and ROS proto-oncogene 1-positive (ROS1+) non-small cell lung cancer (NSCLC), most of these patients eventually relapse with acquired resistance. Therefore, genome-wide CRISPR/Cas9 knockout screening was performed using an ALK+ NSCLC cell line established from pleural effusion without ALK-TKI treatment. After 9 days of ALK-TKI therapy, sequencing analysis was performed, which identified several tumor suppressor genes, such as NF2 or MED12, and multiple candidate genes. Among them, this study focused on ERRFI1, which is known as MIG6 and negatively regulates EGFR signaling. Interestingly, MIG6 loss induced resistance to ALK-TKIs by treatment with quite a low dose of EGF, which is equivalent to plasma concentration, through the upregulation of MAPK and PI3K/AKT/mTOR pathways. Combination therapy with ALK-TKIs and anti-EGFR antibodies could overcome the acquired resistance in both in vivo and in vitro models. In addition, this verified that MIG6 loss induces resistance to ROS1-TKIs in ROS1+ cell lines. This study found a potentially novel factor that plays a role in ALK and ROS1-TKI resistance by activating the EGFR pathway with low-dose ligands.
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Affiliation(s)
- Nobuyuki Kondo
- Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
- Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takahiro Utsumi
- Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuki Shimizu
- Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
- Department of Computational Biology and Medical Science, Graduate School of Frontier Science, The University of Tokyo, Tokyo, Japan
| | - Ai Takemoto
- Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
| | - Tomoko Oh-hara
- Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
| | - Ken Uchibori
- Department of Thoracic Medical Oncology, the Cancer Institute Hospital
| | - Sophia Subat-Motoshi
- Department of Pathology, the Cancer Institute Hospital, and
- Pathology Project for Molecular Targets, Cancer Institute, JFCR, Tokyo, Japan
| | | | - Kengo Takeuchi
- Department of Pathology, the Cancer Institute Hospital, and
- Pathology Project for Molecular Targets, Cancer Institute, JFCR, Tokyo, Japan
| | - Makoto Nishio
- Department of Thoracic Medical Oncology, the Cancer Institute Hospital
| | - Yasunari Miyazaki
- Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ryohei Katayama
- Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
- Department of Computational Biology and Medical Science, Graduate School of Frontier Science, The University of Tokyo, Tokyo, Japan
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Soo RA, Martini JF, van der Wekken AJ, Teraoka S, Ferrara R, Shaw AT, Shepard D, Calella AM, Polli A, Toffalorio F, Tomasini P, Chiu CH, Kowalski DM, Kim HR, Solomon BJ. Early Circulating Tumor DNA Dynamics and Efficacy of Lorlatinib in Patients With Treatment-Naive, Advanced, ALK-Positive NSCLC. J Thorac Oncol 2023; 18:1568-1580. [PMID: 37295609 DOI: 10.1016/j.jtho.2023.05.021] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 05/17/2023] [Accepted: 05/23/2023] [Indexed: 06/12/2023]
Abstract
INTRODUCTION Circulating tumor DNA (ctDNA) has been used as a biomarker for prognostication and response to treatment. Here, we evaluate ctDNA as a potential biomarker for response to lorlatinib, a third-generation ALK tyrosine kinase inhibitor in patients with treatment-naive, advanced, ALK-positive NSCLC in the ongoing phase 3 CROWN study (NCT03052608). METHODS Molecular responses were calculated using mean variant allele frequency (VAF), longitudinal mean change in VAF (dVAF), and ratio to baseline. Efficacy assessments (progression-free survival [PFS] and objective response rate) were paired with individual patient ctDNA and analyzed for association. RESULTS Compared with baseline, mean VAF at week 4 was decreased in both treatment arms. Considering all detected somatic variants, a reduction in dVAF (≤0) was associated with a longer PFS in the lorlatinib arm. The hazard ratio (HR) for a dVAF less than or equal to 0 versus more than 0 was 0.50 (95% confidence interval [CI]: 0.23-1.12) in the lorlatinib arm. A similar association was not observed for crizotinib (HR = 1.00, 95% CI: 0.49-2.03). Comparing molecular responders with nonresponders, patients treated with lorlatinib who had a molecular response had longer PFS (HR = 0.37, 95% CI: 0.16-0.85); patients treated with crizotinib who had a molecular response had similar PFS as those without a molecular response (HR = 1.48, 95% CI: 0.67-3.30). CONCLUSIONS In patients with treatment-naive, advanced, ALK-positive NSCLC, early ctDNA dynamics predicted better outcome with lorlatinib but not with crizotinib. These results suggest that ctDNA may be used to monitor and potentially predict efficacy of lorlatinib treatment.
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Affiliation(s)
- Ross A Soo
- Department of Hematology-Oncology, National University Cancer Institute, Singapore, Singapore.
| | | | - Anthonie J van der Wekken
- Department of Pulmonology, University of Groningen and University Medical Centre Groningen, Groningen, the Netherlands
| | - Shunsuke Teraoka
- Internal Medicine III, Wakayama Medical University, Wakayama, Japan
| | - Roberto Ferrara
- Department of Medical Oncology, IRCCS Foundation, National Cancer Institute, Milan, Italy
| | - Alice T Shaw
- Center for Thoracic Cancers, Massachusetts General Hospital, Boston, Massachusetts
| | - Deborah Shepard
- Global Product Development-Oncology & Rare Disease, Pfizer, La Jolla, California
| | - Anna Maria Calella
- Global Product Development-Oncology & Rare Disease, Pfizer, Milan, Italy
| | - Anna Polli
- Global Product Development-Oncology & Rare Disease, Pfizer, Milan, Italy
| | | | - Pascale Tomasini
- Multidisciplinary Oncology and Therapeutic Innovations Department, Marseille University, Marseille, France
| | - Chao-Hua Chiu
- Division of Pulmonary Medicine, Taipei Cancer Center and Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
| | - Dariusz M Kowalski
- Department of Lung Cancer and Chest Tumors, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Hye Ryun Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea
| | - Benjamin J Solomon
- Department of Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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Iyer SR, Nusser K, Jones K, Shinde P, Keddy C, Beach CZ, Aguero E, Force J, Shinde U, Davare MA. Discovery of oncogenic ROS1 missense mutations with sensitivity to tyrosine kinase inhibitors. EMBO Mol Med 2023; 15:e17367. [PMID: 37587872 PMCID: PMC10565643 DOI: 10.15252/emmm.202217367] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 07/24/2023] [Accepted: 07/26/2023] [Indexed: 08/18/2023] Open
Abstract
ROS1 is the largest receptor tyrosine kinase in the human genome. Rearrangements of the ROS1 gene result in oncogenic ROS1 kinase fusion proteins that are currently the only validated biomarkers for targeted therapy with ROS1 TKIs in patients. While numerous somatic missense mutations in ROS1 exist in the cancer genome, their impact on catalytic activity and pathogenic potential is unknown. We interrogated the AACR Genie database and identified 34 missense mutations in the ROS1 tyrosine kinase domain for further analysis. Our experiments revealed that these mutations have varying effects on ROS1 kinase function, ranging from complete loss to significantly increased catalytic activity. Notably, Asn and Gly substitutions at Asp2113 in the ROS1 kinase domain were found to be TKI-sensitive oncogenic variants in cell-based model systems. In vivo experiments showed that ROS1 D2113N induced tumor formation that was sensitive to crizotinib and lorlatinib, FDA-approved ROS1-TKIs. Collectively, these findings highlight the tumorigenic potential of specific point mutations within the ROS1 kinase domain and their potential as therapeutic targets with FDA-approved ROS1-TKIs.
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Affiliation(s)
- Sudarshan R Iyer
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Papé Family Pediatric Research InstituteOregon Health and Sciences UniversityORPortlandUSA
| | - Kevin Nusser
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Papé Family Pediatric Research InstituteOregon Health and Sciences UniversityORPortlandUSA
| | - Kristen Jones
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Papé Family Pediatric Research InstituteOregon Health and Sciences UniversityORPortlandUSA
| | - Pushkar Shinde
- Department of Chemical PhysiologyOregon Health and Sciences UniversityORPortlandUSA
| | - Clare Keddy
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Papé Family Pediatric Research InstituteOregon Health and Sciences UniversityORPortlandUSA
| | - Catherine Z Beach
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Papé Family Pediatric Research InstituteOregon Health and Sciences UniversityORPortlandUSA
| | - Erin Aguero
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Papé Family Pediatric Research InstituteOregon Health and Sciences UniversityORPortlandUSA
| | - Jeremy Force
- Department of Medicine, Division of Medical Oncology, Duke Cancer InstituteDuke UniversityNCDurhamUSA
| | - Ujwal Shinde
- Department of Chemical PhysiologyOregon Health and Sciences UniversityORPortlandUSA
| | - Monika A Davare
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Papé Family Pediatric Research InstituteOregon Health and Sciences UniversityORPortlandUSA
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Meira DD, de Castro e Caetano MC, Casotti MC, Zetum ASS, Gonçalves AFM, Moreira AR, de Oliveira AH, Pesente F, Santana GM, de Almeida Duque D, Pereira GSC, de Castro GDSC, Pavan IP, Chagas JPS, Bourguignon JHB, de Oliveira JR, Barbosa KRM, Altoé LSC, Louro LS, Merigueti LP, Alves LNR, Machado MRR, Roque MLRO, Prates PS, de Paula Segáua SH, dos Santos Uchiya T, Louro TES, Daleprane VE, Guaitolini YM, Vicente CR, dos Reis Trabach RS, de Araújo BC, dos Santos EDVW, de Paula F, Lopes TJS, de Carvalho EF, Louro ID. Prognostic Factors and Markers in Non-Small Cell Lung Cancer: Recent Progress and Future Challenges. Genes (Basel) 2023; 14:1906. [PMID: 37895255 PMCID: PMC10606762 DOI: 10.3390/genes14101906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 09/29/2023] [Accepted: 10/01/2023] [Indexed: 10/29/2023] Open
Abstract
Lung cancer is a highly aggressive neoplasm and, despite the development of recent therapies, tumor progression and recurrence following the initial response remains unsolved. Several questions remain unanswered about non-small cell lung cancer (NSCLC): (1) Which patients will actually benefit from therapy? (2) What are the predictive factors of response to MAbs and TKIs? (3) What are the best combination strategies with conventional treatments or new antineoplastic drugs? To answer these questions, an integrative literature review was carried out, searching articles in PUBMED, NCBI-PMC, Google Academic, and others. Here, we will examine the molecular genetics of lung cancer, emphasizing NSCLC, and delineate the primary categories of inhibitors based on their molecular targets, alongside the main treatment alternatives depending on the type of acquired resistance. We highlighted new therapies based on epigenetic information and a single-cell approach as a potential source of new biomarkers. The current and future of NSCLC management hinges upon genotyping correct prognostic markers, as well as on the evolution of precision medicine, which guarantees a tailored drug combination with precise targeting.
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Affiliation(s)
- Débora Dummer Meira
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Maria Clara de Castro e Caetano
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Matheus Correia Casotti
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Aléxia Stefani Siqueira Zetum
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - André Felipe Monteiro Gonçalves
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - André Rodrigues Moreira
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Augusto Henrique de Oliveira
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Fellipe Pesente
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Gabriel Mendonça Santana
- Centro de Ciências da Saúde, Curso de Medicina, Universidade Federal do Espírito Santo (UFES), Vitória 29090-040, Brazil
| | - Daniel de Almeida Duque
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Gierleson Santos Cangussu Pereira
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Giulia de Souza Cupertino de Castro
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Isabele Pagani Pavan
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - João Pedro Sarcinelli Chagas
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - José Henrique Borges Bourguignon
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Juliana Ribeiro de Oliveira
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Karen Ruth Michio Barbosa
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Lorena Souza Castro Altoé
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Luana Santos Louro
- Centro de Ciências da Saúde, Curso de Medicina, Universidade Federal do Espírito Santo (UFES), Vitória 29090-040, Brazil
| | - Luiza Poppe Merigueti
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Lyvia Neves Rebello Alves
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Marlon Ramos Rosado Machado
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Maria Luísa Rodrigues Oliveira Roque
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Pedro Santana Prates
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Sayuri Honorio de Paula Segáua
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Taissa dos Santos Uchiya
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Thomas Erik Santos Louro
- Escola Superior de Ciências da Santa Casa de Misericórdia de Vitória (EMESCAM), Curso de Medicina, Vitória 29027-502, Brazil
| | - Vinicius Eduardo Daleprane
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Yasmin Moreto Guaitolini
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Creuza Rachel Vicente
- Departamento de Medicina Social, Universidade Federal do Espírito Santo, Vitória 29090-040, Brazil
| | - Raquel Silva dos Reis Trabach
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Bruno Cancian de Araújo
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Eldamária de Vargas Wolfgramm dos Santos
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Flávia de Paula
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
| | - Tiago José S. Lopes
- Department of Reproductive Biology, National Center for Child Health and Development Research Institute, Tokyo 157-8535, Japan
| | - Elizeu Fagundes de Carvalho
- Instituto de Biologia Roberto Alcântara Gomes (IBRAG), Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro 20551-030, Brazil
| | - Iúri Drumond Louro
- Núcleo de Genética Humana e Molecular, Centro de Ciências Humanas e Naturais, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, Brazil (M.C.C.)
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Liu G, Lam VK. Podcast on Lorlatinib as a First-Line Treatment Option for Patients with ALK-Positive Metastatic NSCLC with Brain Metastasis. Adv Ther 2023; 40:4117-4126. [PMID: 37573276 PMCID: PMC10499938 DOI: 10.1007/s12325-023-02606-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 07/03/2023] [Indexed: 08/14/2023]
Abstract
Brain metastases are especially common in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), with a cumulative incidence of over 50% and associated with a poor prognosis, high symptom burden, and decreased quality of life. Lorlatinib is a brain-penetrant, third-generation ALK tyrosine kinase inhibitor (TKI), which has a high potency against resistance mutations seen with earlier generation ALK TKIs. In 2018, lorlatinib was granted accelerated approval in second- and third-line treatment for use in patients with ALK-positive metastatic NSCLC on the basis of phase 1/2 study results. This initial approval was expanded for first-line treatment of patients with ALK-positive metastatic NSCLC on the basis of the interim analysis of the phase 3 CROWN study showing longer progression-free survival, time to intracranial progression, duration of response, and objective response rate compared with crizotinib. This manuscript is a transcript of our podcast, in which we discuss the clinical significance of controlling the onset of brain metastases, considerations in selecting a first-line therapy option, efficacy and safety observed in patients with and without brain metastases, and rationales for using lorlatinib upfront versus reserving for a later line in therapy.
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Affiliation(s)
- Geoffrey Liu
- Princess Margaret Cancer Centre, Toronto, ON, Canada
| | - Vincent K Lam
- Johns Hopkins Medicine, 201 N. Broadway, Baltimore, MD, 21287, USA.
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Pischedda F, Ghirelli A, Tripathi V, Piccoli G. Negr1-Derived Peptides Trigger ALK Degradation and Halt Neuroblastoma Progression In Vitro and In Vivo. Pharmaceutics 2023; 15:2307. [PMID: 37765276 PMCID: PMC10536585 DOI: 10.3390/pharmaceutics15092307] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 08/24/2023] [Accepted: 09/04/2023] [Indexed: 09/29/2023] Open
Abstract
Neuroblastoma is among the most common childhood cancers. Neuroblastoma in advanced stages is one of the most intractable pediatric cancers, notwithstanding the recent therapeutic advances. ALK mutations are among the leading cause of hereditary neuroblastoma and account for more than 14% of the somatically acquired alterations. ALK kinase activity is currently one of the main targets for pharmacological strategies. However, evidence from ALK fusion-positive lung cancer studies has shown that resistance to ALK inhibition arises during the therapy, causing a relapse within several years. IgLONs are membrane-bound proteins involved in cell-to-cell adhesion. The expression of the IgLON family results altered in different cancers. We found that the IgLON member Negr1 is downregulated in neuroblastoma. The ectopic overexpression of Negr1 impairs neuroblastoma growth in vitro and in vivo. Negr1 exists as a GPI-anchored membrane-bound protein and as a soluble protein released upon metalloprotease cleavage. We generated and characterized a panel of Negr1-derived peptides. The treatment with Negr1 protein and derived peptides induce ALK downregulation and halt neuroblastoma progression in vitro and in vivo.
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Affiliation(s)
| | | | | | - Giovanni Piccoli
- Department of Cellular, Computational and Integrative Biology—CIBIO, University of Trento, 38123 Trento, Italy
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Stiefel J, Kushner BH, Roberts SS, Iglesias-Cardenas F, Kramer K, Modak S. Anaplastic Lymphoma Kinase Inhibitors for Therapy of Neuroblastoma in Adults. JCO Precis Oncol 2023; 7:e2300138. [PMID: 37561984 PMCID: PMC10581627 DOI: 10.1200/po.23.00138] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 05/16/2023] [Accepted: 07/06/2023] [Indexed: 08/12/2023] Open
Abstract
PURPOSE Adult-onset neuroblastoma (AON) differs significantly in biology and clinical behavior from childhood-onset disease. AON poses therapeutic challenges since tolerance of intensive multimodality therapies that are standard of care for pediatric neuroblastoma (NB) is poor. AON is enriched for somatic mutations including anaplastic lymphoma kinase (ALK), deemed to be an oncogenic driver in NB. ALK inhibitors (ALKis), therefore, have the potential to be of therapeutic benefit. The purpose of this study is to report on their use in AON. METHODS A single-center retrospective review of adults with NB receiving ALKi (2012-2022) was performed. Response was evaluated using International Neuroblastoma Response Criteria. RESULTS Fifteen patients with ALK-mutated AON were treated with US Food and Drug Administration-approved ALKi starting at a median age of 34 (16-71) years. Initial ALKi was lorlatinib, crizotinib, and alectinib in seven, five, and three patients respectively; seven received multiple ALKis due to progressive disease/intolerability of one agent. All patients experienced ≥grade 2 adverse events (AEs): crizotinib and alectinib were associated primarily with gastrointestinal AEs, lorlatinib with neurologic AEs, weight gain, and hyperlipidemia resulting in dose reduction or discontinuation of ALKi in several patients. No responses were observed with crizotinib (n = 5 patients), ceritinib, alectinib, or brigatinib (n = 1 each). Of the 13 patients receiving lorlatinib, four, five, and four patients had a complete or partial response (major response rate 69%), and stable disease, respectively. Responses were noted in all disease compartments; complete metabolic response was seen in two L2 patients. Ten of 13 patients remain progression-free at a median of 19 (6-50) months on lorlatinib. Three (two receiving dose-reduced therapy) had progressive disease. Median survival from start of first ALKi was 43 ± 26 months. CONCLUSION ALKis, particularly lorlatinib, are effective treatment options for AON. However, AEs necessitating dose reduction are common.
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Affiliation(s)
- Jessica Stiefel
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Brian H. Kushner
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Stephen S. Roberts
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | | | - Kim Kramer
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Shakeel Modak
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
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Stanzione B, Del Conte A, Bertoli E, De Carlo E, Revelant A, Spina M, Bearz A. Therapeutical Options in ROS1-Rearranged Advanced Non Small Cell Lung Cancer. Int J Mol Sci 2023; 24:11495. [PMID: 37511255 PMCID: PMC10380455 DOI: 10.3390/ijms241411495] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 07/11/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
ROS proto-oncogene 1 (ROS1) rearrangements occur in 0.9-2.6% of patients with non small cell lung cancer (NSCLC), conferring sensitivity to treatment with specific tyrosine-kinase inhibitors (TKI). Crizotinib, a first-generation TKI, was the first target-therapy approved for the first-line treatment of ROS1-positive NSCLC. Recently, entrectinib, a multitarget inhibitor with an anti-ROS1 activity 40 times more potent than crizotinib and better activity on the central nervous system (CNS), received approval for treatment-naive patients. After a median time-to-progression of 5.5-20 months, resistance mechanisms can occur, leading to tumor progression. Therefore, newer generation TKI with greater potency and brain penetration have been developed and are currently under investigation. This review summarizes the current knowledge on clinicopathological characteristics of ROS1-positive NSCLC and its therapeutic options.
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Affiliation(s)
- Brigida Stanzione
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy
| | - Alessandro Del Conte
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy
| | - Elisa Bertoli
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy
| | - Elisa De Carlo
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy
| | - Alberto Revelant
- Department of Radiotherapy, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy
| | - Michele Spina
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy
| | - Alessandra Bearz
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy
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Blandin AF, Giglio R, Graham MS, Garcia G, Malinowski S, Woods JK, Ramkissoon S, Ramkissoon L, Dubois F, Schoolcraft K, Tsai J, Wang D, Jones R, Vogelzang J, Pelton K, Becker S, Watkinson F, Sinai C, Cohen EF, Booker MA, Tolstorukov MY, Haemels V, Goumnerova L, Wright K, Kieran M, Fehnel K, Reardon D, Tauziede-Espariat A, Lulla R, Carcamo B, Chaleff S, Charest A, DeSmet F, Ligon AH, Dubuc A, Pages M, Varlet P, Wen PY, Alexander BM, Chi S, Alexandrescu S, Kittler R, Bachoo R, Bandopadhayay P, Beroukhim R, Ligon KL. ALK Amplification and Rearrangements Are Recurrent Targetable Events in Congenital and Adult Glioblastoma. Clin Cancer Res 2023; 29:2651-2667. [PMID: 36780194 PMCID: PMC10363218 DOI: 10.1158/1078-0432.ccr-21-3521] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/31/2022] [Accepted: 02/07/2023] [Indexed: 02/14/2023]
Abstract
PURPOSE Anaplastic lymphoma kinase (ALK) aberrations have been identified in pediatric-type infant gliomas, but their occurrence across age groups, functional effects, and treatment response has not been broadly established. EXPERIMENTAL DESIGN We performed a comprehensive analysis of ALK expression and genomic aberrations in both newly generated and retrospective data from 371 glioblastomas (156 adult, 205 infant/pediatric, and 10 congenital) with in vitro and in vivo validation of aberrations. RESULTS ALK aberrations at the protein or genomic level were detected in 12% of gliomas (45/371) in a wide age range (0-80 years). Recurrent as well as novel ALK fusions (LRRFIP1-ALK, DCTN1-ALK, PRKD3-ALK) were present in 50% (5/10) of congenital/infant, 1.4% (3/205) of pediatric, and 1.9% (3/156) of adult GBMs. ALK fusions were present as the only candidate driver in congenital/infant GBMs and were sometimes focally amplified. In contrast, adult ALK fusions co-occurred with other oncogenic drivers. No activating ALK mutations were identified in any age group. Novel and recurrent ALK rearrangements promoted STAT3 and ERK1/2 pathways and transformation in vitro and in vivo. ALK-fused GBM cellular and mouse models were responsive to ALK inhibitors, including in patient cells derived from a congenital GBM. Relevant to the treatment of infant gliomas, we showed that ALK protein appears minimally expressed in the forebrain at perinatal stages, and no gross effects on perinatal brain development were seen in pregnant mice treated with the ALK inhibitor ceritinib. CONCLUSIONS These findings support use of brain-penetrant ALK inhibitors in clinical trials across infant, pediatric, and adult GBMs. See related commentary by Mack and Bertrand, p. 2567.
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Affiliation(s)
- Anne-Florence Blandin
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad institute of Harvard and MIT, Cambridge, MA, USA
| | - Ross Giglio
- Dana-Farber Cancer Institute, Boston, MA, USA
| | | | | | | | - Jared K. Woods
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad institute of Harvard and MIT, Cambridge, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | | | | | - Frank Dubois
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad institute of Harvard and MIT, Cambridge, MA, USA
| | | | - Jessica Tsai
- Dana-Farber Cancer Institute, Boston, MA, USA
- Boston Children's Cancer and Blood Disorder Center, Boston, MA, USA
| | - Dayle Wang
- Dana-Farber Cancer Institute, Boston, MA, USA
| | | | | | | | | | | | | | - Elizabeth F Cohen
- Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Matthew A Booker
- Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA, USA
| | | | - Veerle Haemels
- Laboratory for Precision Cancer Medicine, Translational Cell and Tissue Research Unit, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
| | | | - Karen Wright
- Dana-Farber Cancer Institute, Boston, MA, USA
- Boston Children's Cancer and Blood Disorder Center, Boston, MA, USA
| | - Mark Kieran
- Day One Biopharmaceuticals, Brisbane, CA 94005
| | - Katie Fehnel
- Boston Children's Cancer and Blood Disorder Center, Boston, MA, USA
| | | | | | - Rishi Lulla
- Hasbro Children's Hospital, Providence, RI, USA
| | - Benjamin Carcamo
- Texas Tech University, Health Science Center, Paul L. Foster School of Medicine, El Paso, TX, USA
- El Paso Children's Hospital, El Paso, TX, USA
| | | | - Alain Charest
- Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Frederik DeSmet
- Laboratory for Precision Cancer Medicine, Translational Cell and Tissue Research Unit, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
| | - Azra H. Ligon
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
- Boston Children's Cancer and Blood Disorder Center, Boston, MA, USA
| | - Adrian Dubuc
- Dana-Farber Cancer Institute, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | - Melanie Pages
- Department of Genetics, Institute Curie, Paris, France. INSERM U830, Laboratory of Translational Research in Pediatric Oncology, SIREDO Pediatric Oncology Center, Institute Curie, Paris, France
| | | | - Patrick Y. Wen
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Brian M. Alexander
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | - Susan Chi
- Dana-Farber Cancer Institute, Boston, MA, USA
- Boston Children's Cancer and Blood Disorder Center, Boston, MA, USA
| | - Sanda Alexandrescu
- Dana-Farber Cancer Institute, Boston, MA, USA
- Boston Children's Cancer and Blood Disorder Center, Boston, MA, USA
| | - Ralf Kittler
- University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Robert Bachoo
- University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Pratiti Bandopadhayay
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad institute of Harvard and MIT, Cambridge, MA, USA
- Boston Children's Cancer and Blood Disorder Center, Boston, MA, USA
| | - Rameen Beroukhim
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad institute of Harvard and MIT, Cambridge, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | - Keith L. Ligon
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad institute of Harvard and MIT, Cambridge, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
- Boston Children's Cancer and Blood Disorder Center, Boston, MA, USA
- Dana-Farber Cancer Institute, Center for Patient Derived Models (CPDM), Boston, MA, USA
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Fukuda A, Yoshida T. Treatment of advanced ALK-rearranged NSCLC following second-generation ALK-TKI failure. Expert Rev Anticancer Ther 2023; 23:1157-1167. [PMID: 37772744 DOI: 10.1080/14737140.2023.2265566] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 09/27/2023] [Indexed: 09/30/2023]
Abstract
INTRODUCTION Anaplastic lymphoma kinase (ALK) gene rearrangement is detected in approximately 3-5% of non-small cell lung cancer (NSCLC) cases. Tyrosine kinase inhibitors (TKIs) targeting ALK rearrangement (ALK-TKIs) have shown significant efficacy and improved the survival of patients with NSCLC exhibiting ALK rearrangement. However, almost all patients exhibit disease progression during TKI therapy owing to resistance acquired through various molecular mechanisms, including both ALK-dependent and ALK-independent. AREAS COVERED Here, we review the mechanisms underlying resistance to second-generation ALK-TKIs, and the clinical management strategies following resistance in patients with ALK rearrangement-positive NSCLC. EXPERT OPINION Treatment strategies following the failure of second-generation ALK-TKIs failure should be based on resistant mechanisms. For patients with ALK mutations who exhibit resistance to second-generation ALK-TKIs, lorlatinib is the primary treatment option. However, the identification of resistance profiles of second-generation ALK-TKIs can aid in the selection of an appropriate treatment strategy. In cases of ALK-dependent resistance mutations, lorlatinib could be the first choice as it exhibits the broadest coverage of mutations that lead to resistance against second-generation ALK-TKIs, such as G1202R, and L1196M. In cases of no resistance mutations, atezolizumab, bevacizumab, and platinum-based chemotherapy could be the alternative treatment options.
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Affiliation(s)
- Akito Fukuda
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Tatsuya Yoshida
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
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Guo J, Zhou Y, Lu X. Advances in protein kinase drug discovery through targeting gatekeeper mutations. Expert Opin Drug Discov 2023; 18:1349-1366. [PMID: 37811637 DOI: 10.1080/17460441.2023.2265303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 09/27/2023] [Indexed: 10/10/2023]
Abstract
INTRODUCTION Acquired resistance caused by gatekeeper mutations has become a major challenge for approved kinase inhibitors used in the clinic. Consequently, the development of new-generation inhibitors or degraders to overcome clinical resistance has become an important research focus for the field. AREAS COVERED This review summarizes the common gatekeeper mutations in druggable kinases and the constantly evolving inhibitors or degraders designed to overcome single or double mutations of gatekeeper residues. Furthermore, the authors provide their perspectives on the medicinal chemistry strategies for addressing clinical resistance with gatekeeper mutations. EXPERT OPINION The authors suggest optimizing kinase inhibitors to interact effectively with gatekeeper residues, altering the binding mode or binding pocket to avoid steric clashes, improving binding affinity with the target, utilizing protein degraders, and developing combination therapy. These approaches have the potential to be effective in overcoming resistance due to gatekeeper residues.
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Affiliation(s)
- Jing Guo
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, China
| | - Yang Zhou
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, China
| | - Xiaoyun Lu
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, China
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Zhao S, Li J, Xia Q, Liu K, Dong Z. New perspectives for targeting therapy in ALK-positive human cancers. Oncogene 2023:10.1038/s41388-023-02712-8. [PMID: 37149665 DOI: 10.1038/s41388-023-02712-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 04/27/2023] [Indexed: 05/08/2023]
Abstract
Anaplastic lymphoma kinase (ALK) is a member of the insulin receptor protein-tyrosine kinase superfamily and was first discovered in anaplastic large-cell lymphoma (ALCL). ALK alterations, including fusions, over-expression and mutations, are highly associated with cancer initiation and progression. This kinase plays an important role in different cancers, from very rare to the more prevalent non-small cell lung cancers. Several ALK inhibitors have been developed and received Food and Drug Administration (FDA) approval. However, like other drugs used in targeted therapies, ALK inhibitors inevitably encounter cancer cell resistance. Therefore, monoclonal antibody screening based on extracellular domain or combination therapies may provide viable alternatives for treating ALK-positive tumors. In this review, we discuss the current understanding of wild-type ALK and fusion protein structures, the pathological functions of ALK, ALK target therapy, drug resistance and future therapeutic directions.
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Affiliation(s)
- Simin Zhao
- Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, PR China
| | - Jian Li
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, PR China
| | - Qingxin Xia
- Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, PR China.
| | - Kangdong Liu
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, PR China.
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, Henan, PR China.
- Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan, PR China.
| | - Zigang Dong
- Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, PR China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, PR China.
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, Henan, PR China.
- Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan, PR China.
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50
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Gao Y, Jiang B, Kim H, Berberich MJ, Che J, Donovan KA, Hatcher JM, Huerta F, Kwiatkowski NP, Liu Y, Liuni PP, Metivier RJ, Murali VK, Nowak RP, Zhang T, Fischer ES, Gray NS, Jones LH. Catalytic Degraders Effectively Address Kinase Site Mutations in EML4-ALK Oncogenic Fusions. J Med Chem 2023; 66:5524-5535. [PMID: 37036171 PMCID: PMC11827123 DOI: 10.1021/acs.jmedchem.2c01864] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2023]
Abstract
Heterobifunctional degraders, known as proteolysis targeting chimeras (PROTACs), theoretically possess a catalytic mode-of-action, yet few studies have either confirmed or exploited this potential advantage of event-driven pharmacology. Degraders of oncogenic EML4-ALK fusions were developed by conjugating ALK inhibitors to cereblon ligands. Simultaneous optimization of pharmacology and compound properties using ternary complex modeling and physicochemical considerations yielded multiple catalytic degraders that were more resilient to clinically relevant ATP-binding site mutations than kinase inhibitor drugs. Our strategy culminated in the design of the orally bioavailable derivative CPD-1224 that avoided hemolysis (a feature of detergent-like PROTACs), degraded the otherwise recalcitrant mutant L1196M/G1202R in vivo, and commensurately slowed tumor growth, while the third generation ALK inhibitor drug lorlatinib had no effect. These results validate our original therapeutic hypothesis by exemplifying opportunities for catalytic degraders to proactively address binding site resistant mutations in cancer.
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Affiliation(s)
- Yang Gao
- Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States
| | - Baishan Jiang
- Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States
| | - Hellen Kim
- Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
| | - Matthew J Berberich
- Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
| | - Jianwei Che
- Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States
| | - Katherine A Donovan
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
| | - John M Hatcher
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
| | - Fidel Huerta
- Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
| | - Nicholas P Kwiatkowski
- Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
| | - Yingpeng Liu
- Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States
| | - Peter P Liuni
- Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
| | - Rebecca J Metivier
- Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
| | - Vineeth K Murali
- Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
| | - Radosław P Nowak
- Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States
| | - Tinghu Zhang
- Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, California 94305, United States
| | - Eric S Fischer
- Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
| | - Nathanael S Gray
- Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, California 94305, United States
| | - Lyn H Jones
- Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States
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