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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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Xie J, Gao Y, Xu W, Zhu J. Mechanisms of Resistance to ALK Inhibitors and Corresponding Treatment Strategies in Lung Cancer. Int J Gen Med 2025; 18:2151-2171. [PMID: 40259931 PMCID: PMC12010037 DOI: 10.2147/ijgm.s512395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 04/02/2025] [Indexed: 04/23/2025] Open
Abstract
Lung cancer continues to be a leading cause of cancer-related mortality and morbidity worldwide. The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene accounts for approximately 3%-5% of gene mutation types. Targeted therapies for ALK mutations have made significant advancements in recent decades, enabling a considerable number of patients to achieve the goal of five-year survival benefits. However, overcoming the drug resistance that arises with current ALK tyrosine kinase inhibitors (TKIs) remain a major challenge in ALK-targeted therapies. In this review, we briefly discuss the primary and secondary mechanisms of resistance to ALK-TKIs, and explore treatment strategies based on progressive resistance models. Meanwhile, novel drugs and combination therapies are being actively researched and developed to address these challenges. The aim is to offer new insights into the mechanisms of resistance and the corresponding treatment strategies to ALK inhibitors.
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Affiliation(s)
- Jiajun Xie
- Department of Respiratory and Critical Care Medicine, Mian yang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, People’s Republic of China
| | - Yinghao Gao
- Department of pulmonology, Mianyang hospital of T.C.M, Mianyang, People’s Republic of China
| | - Weiguo Xu
- Department of Respiratory and Critical Care Medicine, Mian yang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, People’s Republic of China
| | - Jing Zhu
- Department of Respiratory and Critical Care Medicine, Mian yang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, People’s Republic of China
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Vitale A, Vita E, Stefani A, Cancellieri A, Lococo F, Tortora G, Bria E. Overcoming amplification-mediated resistance to sotorasib by dose re-escalation in KRAS G12C mutant NSCLC: a case report. Oncologist 2025; 30:oyaf030. [PMID: 40110764 PMCID: PMC11923590 DOI: 10.1093/oncolo/oyaf030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 01/30/2025] [Indexed: 03/22/2025] Open
Abstract
Precision oncology has transformed non-small cell lung cancer (NSCLC) treatment by tailoring therapies to the genomic profile of the disease, significantly improving clinical outcomes. However, acquired resistance to molecularly targeted therapies remains a major challenge. This report details a 69-year-old woman with KRAS G12C-mutant metastatic NSCLC who developed resistance to sotorasib, a KRAS G12C inhibitor. Initially responding to the standard dose of 960 mg, the patient required a dose reduction to 480 mg due to liver toxicity. After 20 months, oligoprogression occurred, managed through surgical resection. Molecular analysis of the resected tissue identified KRAS amplification as a resistance mechanism. Following disease progression, re-escalation of sotorasib to 960 mg led to renewed tumor response without additional toxicity. This case highlights dose re-escalation as a potential strategy to address resistance in selected patients and underscores the critical role of molecular profiling and personalized approaches in optimizing targeted NSCLC treatments.
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Affiliation(s)
- Antonio Vitale
- Comprehensive Cancer Center, Medical Oncology Department, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Faculty of Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Emanuele Vita
- Comprehensive Cancer Center, Medical Oncology Department, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Faculty of Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Alessio Stefani
- Comprehensive Cancer Center, Medical Oncology Department, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Faculty of Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Alessandra Cancellieri
- Pathology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Filippo Lococo
- Faculty of Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Thoracic Surgery Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Giampaolo Tortora
- Comprehensive Cancer Center, Medical Oncology Department, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Faculty of Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Emilio Bria
- Comprehensive Cancer Center, Medical Oncology Department, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Faculty of Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Medical Oncology, Ospedale Isola Tiberina – Gemelli Isola, 00186 Rome, Italy
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4
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Yang Q, Zhao D, Ju L, Cao P, Wei J, Liu Z. Brigatinib can inhibit proliferation and induce apoptosis of human immortalized keratinocyte cells. Front Pharmacol 2025; 16:1524277. [PMID: 40041486 PMCID: PMC11876137 DOI: 10.3389/fphar.2025.1524277] [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: 11/07/2024] [Accepted: 01/21/2025] [Indexed: 03/06/2025] Open
Abstract
Background Brigatinib is approved in multiple countries for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Despite its superior efficacy, the dermal toxicities caused by brigatinib cannot be overlooked. However, its underlying mechanism remains unknown. Methods The effects of brigatinib on the proliferation ability of human immortalized keratinocyte (HaCaT) cells were evaluated using Cell Counting Kit-8 (CCK-8) proliferation, colony formation, and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assays. The effects of brigatinib on apoptosis were detected using Annexin FITC/PI and Acridine Orange (AO) staining assays. Cell cycle was assessed with flow cytometry. An analysis of transcriptome by RNA sequencing procedures (RNA-seq) was performed to reveal the key regulatory genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to find out the biological function and related signal pathways. The expressions of amphiregulin, epiregulin and transforming growth factor alpha (TGFA) and the protein levels of Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and Cleaved-Caspase three were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot assay. Results Brigatinib inhibits cell proliferation with an IC50 value of 2.9 μmol/L and significantly increases apoptosis rates. Transcriptome sequencing (RNA-seq) indicates that brigatinib could significantly downregulate the expression of amphiregulin, epiregulin and TGFA. In addition, we demonstrated that brigatinib reduced the protein expression of amphiregulin, epiregulin, TGFA, PI3K, AKT and phosphorylated AKT (p-AKT). Conclusion This study confirms the inhibition of HaCaT cells growth and progression by brigatinib and highlights the potential value of the PI3K/AKT pathway as a therapeutic target for brigatinib-induced dermal toxicities.
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Affiliation(s)
- Qi Yang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Dan Zhao
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Linjie Ju
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Peng Cao
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jifu Wei
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Zhixian Liu
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
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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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6
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Tobiášová K, Barthová M, Janáková Ľ, Lešková K, Farkašová A, Loderer D, Grendár M, Plank L. Discordant ALK Status in Non-Small Cell Lung Carcinoma: A Detailed Reevaluation Comparing IHC, FISH, and NGS Analyses. Int J Mol Sci 2024; 25:8168. [PMID: 39125737 PMCID: PMC11312000 DOI: 10.3390/ijms25158168] [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: 06/14/2024] [Revised: 07/19/2024] [Accepted: 07/23/2024] [Indexed: 08/12/2024] Open
Abstract
ALK detection was performed on 2813 EGFR-unmutated NSCLC cases by simultaneous use of immunohistochemistry (VENTANA® anti-ALK D5F3, Roche Molecular Systems, Inc., Rotkreuz, Switzerland) and fluorescence in situ hybridization with the ALK break apart and the ALK/EML4 fusion probe (ZytoVision, Bremerhaven, Germany). A total of 33 cases were positive discordant (FISH-positive, IHC-negative) and 17 cases were negative discordant (FISH-negative, IHC-positive). This study's aim was to reevaluate the methods used and compare discordant samples to positive concordant samples in order to ellucidate the differences. FISH signal variants were examined and compared. Positive discordant cases featured one pattern of ALK rearrangement in 41.4%, two patterns in 48.3%, and three patterns in 10.3% of analysed samples, with a higher variability of detected patterns and a higher number of ALK copy gains. Positive concordant cases displayed one pattern of rearrangement in 82%, two patterns in 17.8%, and three patterns in 0.6% of analysed samples. The association between number of patterns and concordance/discordance was statistically significant (p < 0.05). Eleven positive discordant and two negative concordant cases underwent NGS analysis, which resulted in identification of ALK fusion in one positive discordant and two negative discordant cases. Positive protein expression regardless of FISH result correlated more with a positive NGS result compared to samples with a positive FISH result with negative protein expression. FISH analysis was able to detect atypical or heterogenous patterns of rearrangement in a proportion of cases with negative protein expression, which may be associated with more extensive genetic alterations rather than true ALK rearrangement.
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Affiliation(s)
- Katarína Tobiášová
- Department of Pathological Anatomy, University Hospital Martin, Jessenius Faculty of Medicine, Comenius University, 036 01 Martin, Slovakia; (K.T.)
| | - Martina Barthová
- Department of Pathological Anatomy, University Hospital Martin, Jessenius Faculty of Medicine, Comenius University, 036 01 Martin, Slovakia; (K.T.)
| | - Ľuboslava Janáková
- Department of Pathological Anatomy, University Hospital Martin, Jessenius Faculty of Medicine, Comenius University, 036 01 Martin, Slovakia; (K.T.)
| | - Katarína Lešková
- Department of Pathological Anatomy, University Hospital Martin, Jessenius Faculty of Medicine, Comenius University, 036 01 Martin, Slovakia; (K.T.)
| | | | - Dušan Loderer
- Biomedical Centre Martin—BioMed Martin, Jessenius Faculty of Medicine, Comenius University, 036 01 Martin, Slovakia
| | - Marián Grendár
- Biomedical Centre Martin—BioMed Martin, Jessenius Faculty of Medicine, Comenius University, 036 01 Martin, Slovakia
| | - Lukáš Plank
- Department of Pathological Anatomy, University Hospital Martin, Jessenius Faculty of Medicine, Comenius University, 036 01 Martin, Slovakia; (K.T.)
- Martin’s Biopsy Center, Ltd., 036 01 Martin, Slovakia
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Attwa MW, Abdelhameed AS, Kadi AA. Characterization of the in vitro metabolic profile of nazartinib in HLMs using UPLC-MS/MS method: In silico metabolic lability and DEREK structural alerts screening using StarDrop software. Heliyon 2024; 10:e34109. [PMID: 39091946 PMCID: PMC11292529 DOI: 10.1016/j.heliyon.2024.e34109] [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: 01/20/2024] [Revised: 06/30/2024] [Accepted: 07/03/2024] [Indexed: 08/04/2024] Open
Abstract
The orally given, irreversible, third-generation inhibitor of the epidermal growth factor receptor (EGFR), known as Nazartinib (EGF816), is now undergoing investigation in Phase II clinical trials conducted by Novartis for Non-Small Cell Lung Cancer. The primary aim of the current research was to establish a rapid, specific, environmentally friendly, and highly versatile UPLC-MS/MS methodology for the determination of nazartinib (NZT) levels in human liver microsomes (HLMs). Subsequently, same approach was used to examine the metabolic stability of NZT. The UPLC-MS/MS method employed in HLMs was validated as stated in the bioanalytical method validation criteria outlined by the US- FDA. The evaluation of the metabolic stability of NZT and the identification of potentially structural alarms were performed using the StarDrop software package that includes the P450 and DEREK software. The calibration curve for NZT showed a linearity in the range from 1 to 3000 ng/mL. The inter-day accuracy and precision exhibited a range of values between -4.33 % and 4.43 %, whereas the intra-day accuracy and precision shown a range of values between -2.78 % and 7.10 %. The sensitivity of the developed approach was verified through the determination of a LLOQ of 0.39 ng/mL. The intrinsic clearance and in vitro half-life of NZT were assessed to be 46.48 mL/min/kg and 17.44 min, respectively. In our preceding inquiry, we have effectively discerned the bioactivation center, denoted by the carbon atom between the unsaturated conjugated system and aliphatic linear tertiary amine. In the context of computational software, making minor adjustments or substituting the dimethylamino-butenoyl moiety throughout the drug design process may increase the metabolic stability and safety properties of new synthesized derivatives. The efficiency of utilizing different in silico software approaches to conserve resources and reduce effort was proved by the outcomes attained from in vitro incubation experiments and the use of NZT in silico software.
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Affiliation(s)
- Mohamed W. Attwa
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Ali S. Abdelhameed
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Adnan A. Kadi
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
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8
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Combarel D, Dousset L, Bouchet S, Ferrer F, Tetu P, Lebbe C, Ciccolini J, Meyer N, Paci A. Tyrosine kinase inhibitors in cancers: Treatment optimization - Part I. Crit Rev Oncol Hematol 2024; 199:104384. [PMID: 38762217 DOI: 10.1016/j.critrevonc.2024.104384] [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: 01/24/2024] [Revised: 05/02/2024] [Accepted: 05/03/2024] [Indexed: 05/20/2024] Open
Abstract
A multitude of TKI has been developed and approved targeting various oncogenetic alterations. While these have provided improvements in efficacy compared with conventional chemotherapies, resistance to targeted therapies occurs. Mutations in the kinase domain result in the inability of TKI to inactivate the protein kinase. Also, gene amplification, increased protein expression and downstream activation or bypassing of signalling pathways are commonly reported mechanisms of resistance. Improved understanding of mechanisms involved in TKI resistance has resulted in the development of new generations of targeted agents. In a race against time, the search for new, more potent and efficient drugs, and/or combinations of drugs, remains necessary as new resistance mechanisms to the latest generation of TKI emerge. This review examines the various generations of TKI approved to date and their common mechanisms of resistance, focusing on TKI targeting BCR-ABL, epidermal growth factor receptor, anaplastic lymphoma kinase and BRAF/MEK tyrosine kinases.
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Affiliation(s)
- David Combarel
- Service de Pharmacologie, Département de Biologie et Pathologie médicales, Gustave Roussy, Villejuif 94805, France; Service de Pharmacocinétique, Faculté de Pharmacie, Université Paris Saclay, Châtenay-Malabry 92 296, France
| | - Léa Dousset
- Dermatology Department, Bordeaux University Hospital, Bordeaux, France
| | - Stéphane Bouchet
- Département de Pharmacologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
| | - Florent Ferrer
- Department of Pharmacology, Clermont-Ferrand University Hospital, Clermont-Ferrand, France; SMARTc Unit, CRCM Inserm U1068, Aix Marseille Univ and APHM, Marseille, France
| | - Pauline Tetu
- Department of Dermatology, APHP Dermatology, Paris 7 Diderot University, INSERM U976, Hôpital Saint-Louis, Paris, France
| | - Céleste Lebbe
- Department of Dermatology, APHP Dermatology, Paris 7 Diderot University, INSERM U976, Hôpital Saint-Louis, Paris, France
| | - Joseph Ciccolini
- SMARTc Unit, CRCM Inserm U1068, Aix Marseille Univ and APHM, Marseille, France
| | - Nicolas Meyer
- Université Paul Sabatier-Toulouse III, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1037-CRCT, Toulouse, France
| | - Angelo Paci
- Service de Pharmacologie, Département de Biologie et Pathologie médicales, Gustave Roussy, Villejuif 94805, France; Service de Pharmacocinétique, Faculté de Pharmacie, Université Paris Saclay, Châtenay-Malabry 92 296, France.
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9
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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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10
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Liu W, Huo G, Chen P. Cost-effectiveness of first-line versus second-line use of brigatinib followed by lorlatinib in patients with ALK-positive non-small cell lung cancer. Front Public Health 2024; 12:1213318. [PMID: 38435286 PMCID: PMC10906082 DOI: 10.3389/fpubh.2024.1213318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 02/05/2024] [Indexed: 03/05/2024] Open
Abstract
Background The ALTA-1 L trial and EXP-3B arm of NCT01970865 trial found that both brigatinib and lorlatinib showed durable and robust responses in treating ALK-positive non-small cell lung cancer (NSCLC) patients. However, brigatinib and lorlatinib treatments are costly and need indefinite administration until the disease progression. Thus, it remains uncertain whether using brigatinib followed by lorlatinib before chemotherapy is cost-effective compared to reserving these two drugs until progression after chemotherapy. Methods We used a Markov model to assess clinical outcomes and healthcare costs of treating ALK-positive NSCLC individuals with brigatinib followed by lorlatinib before chemotherapy versus a strategy of reserving these drugs until progression after chemotherapy. Transition probabilities were estimated using parametric survival modeling based on multiple clinical trials. The drug acquisition costs, adverse events costs, administration costs were extracted from published studies before and publicly available data. We calculated lifetime direct healthcare costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios from the perspective of a United States payer. Results Our base-case analysis indicated that the incremental cost-effectiveness ratios of using first-line brigatinib followed by lorlatinib compared with second-line brigatinib followed by lorlatinib is $-400,722.09/QALY which meant that second-line brigatinib followed by lorlatinib had less costs and better outcomes. Univariate sensitivity analysis indicated the results were most sensitive to the cost of brigatinib. Probability sensitivity analysis revealed that using brigatinib followed by lorlatinib before chemotherapy had a 0% probability of cost-effectiveness versus delaying these two drugs until progression after chemotherapy at a willingness-to-pay threshold of $150,000 per QALY. Sensitivity analyses conducted revealed the robustness of this result, as incremental cost-effectiveness ratios never exceeded the willingness-to-pay threshold. Conclusion Using brigatinib as first-line treatment followed by lorlatinib for ALK-positive NSCLC may not be cost-effective given current pricing from the perspective of a United States payer. Delaying brigatinib followed by lorlatinib until subsequent lines of treatment may be a reasonable strategy that could limit healthcare costs without affecting clinical outcomes. More mature data are needed to better estimate cost-effectiveness in this setting.
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Affiliation(s)
- Wenjie Liu
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Gengwei Huo
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Peng Chen
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
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11
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Elshatlawy M, Sampson J, Clarke K, Bayliss R. EML4-ALK biology and drug resistance in non-small cell lung cancer: a new phase of discoveries. Mol Oncol 2023; 17:950-963. [PMID: 37149843 PMCID: PMC10257413 DOI: 10.1002/1878-0261.13446] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 04/05/2023] [Accepted: 05/05/2023] [Indexed: 05/08/2023] Open
Abstract
Anaplastic lymphoma kinase (ALK) can be driven to oncogenic activity by different types of mutational events such as point-mutations, for example F1174L in neuroblastoma, and gene fusions, for example with echinoderm microtubule-associated protein-like 4 (EML4) in non-small cell lung cancer (NSCLC). EML4-ALK variants result from different breakpoints, generating fusions of different sizes and properties. The most common variants (Variant 1 and Variant 3) form cellular compartments with distinct physical properties. The presence of a partial, probably misfolded beta-propeller domain in variant 1 confers solid-like properties to the compartments it forms, greater dependence on Hsp90 for protein stability and higher cell sensitivity to ALK tyrosine kinase inhibitors (TKIs). These differences translate to the clinic because variant 3, on average, worsens patient prognosis and increases metastatic risk. Latest generation ALK-TKIs are beneficial for most patients with EML4-ALK fusions. However, resistance to ALK inhibitors can occur via point-mutations within the kinase domain of the EML4-ALK fusion, for example G1202R, reducing inhibitor effectiveness. Here, we discuss the biology of EML4-ALK variants, their impact on treatment response, ALK-TKI drug resistance mechanisms and potential combination therapies.
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Affiliation(s)
- Mariam Elshatlawy
- Faculty of Biological Sciences, School of Molecular and Cellular BiologyUniversity of LeedsUK
| | - Josephina Sampson
- Faculty of Biological Sciences, School of Molecular and Cellular BiologyUniversity of LeedsUK
- Astbury Centre for Structural Molecular BiologyUniversity of LeedsUK
| | - Katy Clarke
- Leeds Cancer Center, St.James' University HospitalLeeds Teaching Hospitals NHS TrustUK
| | - Richard Bayliss
- Faculty of Biological Sciences, School of Molecular and Cellular BiologyUniversity of LeedsUK
- Astbury Centre for Structural Molecular BiologyUniversity of LeedsUK
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12
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Lei Z, Tian Q, Teng Q, Wurpel JND, Zeng L, Pan Y, Chen Z. Understanding and targeting resistance mechanisms in cancer. MedComm (Beijing) 2023; 4:e265. [PMID: 37229486 PMCID: PMC10203373 DOI: 10.1002/mco2.265] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 03/05/2023] [Accepted: 03/23/2023] [Indexed: 05/27/2023] Open
Abstract
Resistance to cancer therapies has been a commonly observed phenomenon in clinical practice, which is one of the major causes of treatment failure and poor patient survival. The reduced responsiveness of cancer cells is a multifaceted phenomenon that can arise from genetic, epigenetic, and microenvironmental factors. Various mechanisms have been discovered and extensively studied, including drug inactivation, reduced intracellular drug accumulation by reduced uptake or increased efflux, drug target alteration, activation of compensatory pathways for cell survival, regulation of DNA repair and cell death, tumor plasticity, and the regulation from tumor microenvironments (TMEs). To overcome cancer resistance, a variety of strategies have been proposed, which are designed to enhance the effectiveness of cancer treatment or reduce drug resistance. These include identifying biomarkers that can predict drug response and resistance, identifying new targets, developing new targeted drugs, combination therapies targeting multiple signaling pathways, and modulating the TME. The present article focuses on the different mechanisms of drug resistance in cancer and the corresponding tackling approaches with recent updates. Perspectives on polytherapy targeting multiple resistance mechanisms, novel nanoparticle delivery systems, and advanced drug design tools for overcoming resistance are also reviewed.
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Affiliation(s)
- Zi‐Ning Lei
- PrecisionMedicine CenterScientific Research CenterThe Seventh Affiliated HospitalSun Yat‐Sen UniversityShenzhenP. R. China
- Department of Pharmaceutical SciencesCollege of Pharmacy and Health SciencesSt. John's UniversityQueensNew YorkUSA
| | - Qin Tian
- PrecisionMedicine CenterScientific Research CenterThe Seventh Affiliated HospitalSun Yat‐Sen UniversityShenzhenP. R. China
| | - Qiu‐Xu Teng
- Department of Pharmaceutical SciencesCollege of Pharmacy and Health SciencesSt. John's UniversityQueensNew YorkUSA
| | - John N. D. Wurpel
- Department of Pharmaceutical SciencesCollege of Pharmacy and Health SciencesSt. John's UniversityQueensNew YorkUSA
| | - Leli Zeng
- PrecisionMedicine CenterScientific Research CenterThe Seventh Affiliated HospitalSun Yat‐Sen UniversityShenzhenP. R. China
| | - Yihang Pan
- PrecisionMedicine CenterScientific Research CenterThe Seventh Affiliated HospitalSun Yat‐Sen UniversityShenzhenP. R. China
| | - Zhe‐Sheng Chen
- Department of Pharmaceutical SciencesCollege of Pharmacy and Health SciencesSt. John's UniversityQueensNew YorkUSA
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13
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Li Y, Lv Y, Zhang C, Fu B, Liu Y, Hu J. Recent advances in the development of dual ALK/ROS1 inhibitors for non-small cell lung cancer therapy. Eur J Med Chem 2023; 257:115477. [PMID: 37210839 DOI: 10.1016/j.ejmech.2023.115477] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/09/2023] [Accepted: 05/10/2023] [Indexed: 05/23/2023]
Abstract
As a member of the insulin-receptor superfamily, ALK plays an important role in regulating the growth, proliferation, and survival of cells. ROS1 is highly homologous with ALK, and can also regulate normal physiological activities of cells. The overexpression of both is closely related to the development and metastasis of tumors. Therefore, ALK and ROS1 may serve as important therapeutic targets in non-small cell lung cancer (NSCLC). Clinically, many ALK inhibitors have shown powerful therapeutic efficacy in ALK and ROS1-positive NSCLC patients. However, after some time, patients inevitably develop drug resistance, leading to treatment failure. There are no significant drug breakthroughs in solving the problem of drug-resistant mutations. In this review, we summarize the chemical structural features of several novel dual ALK/ROS1 inhibitors, their inhibitory effect on ALK and ROS1 kinases, and future treatment strategies for patients with ALK and ROS1 inhibitor-resistant mutations.
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Affiliation(s)
- Yingxue Li
- Weifang Medical University, No.7166 Baotong Road, Weifang, 261053, PR China
| | - Yanna Lv
- Weifang Medical University, No.7166 Baotong Road, Weifang, 261053, PR China
| | - Cheng Zhang
- Weifang Medical University, No.7166 Baotong Road, Weifang, 261053, PR China
| | - Binyu Fu
- Weifang Medical University, No.7166 Baotong Road, Weifang, 261053, PR China
| | - Yue Liu
- Weifang Medical University, No.7166 Baotong Road, Weifang, 261053, PR China.
| | - Jinxing Hu
- Weifang Medical University, No.7166 Baotong Road, Weifang, 261053, PR China.
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14
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Gao Y, Liu T, Liu J, Yang Y, Sun K, Li Z, Zhai X, Zuo D. ZYY-B-2, a novel ALK inhibitor, overcomes resistance to ceritinib by inhibiting P-gp function and induces apoptosis through mitochondrial pathway in ceritinib-resistant H2228 cells. Chem Biol Interact 2023; 379:110516. [PMID: 37116853 DOI: 10.1016/j.cbi.2023.110516] [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: 01/16/2023] [Revised: 04/04/2023] [Accepted: 04/25/2023] [Indexed: 04/30/2023]
Abstract
Targeting the Echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK) fusion gene is a promising therapeutic strategy for non-small-cell lung cancer (NSCLC) patients. With the advent of the first- and second-generation ALK inhibitors, the mortality rate of lung cancer has shown a downward trend, but almost inevitably, patients will eventually develop resistance, which severely limits the clinical application. Hence, developing new ALK inhibitors which can overcome resistance is essential. Here, we synthesized a novel ALK inhibitor 1-[4-[[5-Chloro-4-[[2-[(1-methylethyl)sulfonyl]phenyl]amino]-2-pyrimidinyl]amino]-3-methoxyphenyl]-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-2-imidazolidinone (ZYY-B-2) based on the structure of the second-generation ALK inhibitor ceritinib. ZYY-B-2 exhibited impressive anti-proliferative effect in the EML4-ALK positive H2228 cells and ceritinib-resistant H2228 (H2228/Cer) cells. Meanwhile, ZYY-B-2 inhibited the activation of p-ALK in a concentration-dependent manner, and inactivated its downstream target proteins p-AKT and p-ERK to inhibit cell proliferation. Subsequently, we found that ZYY-B-2 blocked H2228 cells and H2228/Cer cells in G0/G1 phase and induced cells to undergo apoptosis through the mitochondrial pathway. The ability of its anti-proliferation and pro-apoptosis was significantly stronger than the second generation ALK inhibitor ceritinib. In addition, high expression of P-gp was found in H2228/Cer cells compared with H2228 cells. ZYY-B-2 could inhibit the expression of P-gp in a dose-dependent manner to overcome ceritinib resistance, and the suppression effect of ZYY-B-2 on P-gp might be related to its inhibition of PI3K/AKT signaling pathway. In summary, ZYY-B-2, a promising ALK inhibitor, shows potent activity against ceritinib-resistant cells, which provides experimental and theoretical basis for the further development of new ALK inhibitors.
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Affiliation(s)
- Ying Gao
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China
| | - Tong Liu
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China
| | - Jingang Liu
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China
| | - Yuying Yang
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China
| | - Keyan Sun
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China
| | - Zengqiang Li
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China
| | - Xin Zhai
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
| | - Daiying Zuo
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
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15
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Yang Y, Zheng Q, Wang X, Zhao S, Huang W, Jia L, Ma C, Liu S, Zhang Y, Xin Q, Sun Y, Zheng S. Iruplinalkib (WX‑0593), a novel ALK/ROS1 inhibitor, overcomes crizotinib resistance in preclinical models for non-small cell lung cancer. Invest New Drugs 2023; 41:254-266. [PMID: 37036582 PMCID: PMC10140010 DOI: 10.1007/s10637-023-01350-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 03/16/2023] [Indexed: 04/11/2023]
Abstract
Despite remarkable initial responses of anaplastic lymphoma kinase (ALK) inhibitors in ALK-positive non-small cell lung cancer (NSCLC) patients, cancers eventually develop resistance within one to two years. This study aimed to compare the properties of iruplinalkib (WX‑0593) with other ALK inhibitors and report the comprehensive characterization of iruplinalkib against the crizotinib resistance. The inhibitory effect of iruplinalkib on kinase activity was detected. A kinase screen was performed to evaluate the selectivity of iruplinalkib. The effect of iruplinalkib on related signal transduction pathways of ALK and c-ros oncogene 1 (ROS1) kinases was examined. The cellular and in vivo activities of ALK inhibitors were compared in engineered cancer-derived cell lines and in mice xenograft models, respectively. Human hepatocytes derived from three donors were used for evaluating hepatic enzyme inducing activity. HEK293 cell lines expressing transportors were used to invesigated the drug interaction potential mediated by several transporters. The results showed iruplinalkib potently inhibited the tyrosine autophosphorylation of wild-type ALK, ALKL1196M, ALKC1156Y and epidermal growth factor receptor (EGFR)L858R/T790M. The inhibitory effects of iruplinalkib in patient-derived xenograft and cell line-derived xenograft models were observed. Moreover, iruplinalkib showed robust antitumor effects in BALB/c nude mice xenograft models with ALK-/ROS1-positive tumors implanted subcutaneously, and the tumor suppressive effects in crizotinib-resistant model was significantly better than that of brigatinib. Iruplinalkib did not induce CYP1A2, CYP2B6 and CYP3A4 at therapeutic concentration, and was also a strong inhibitor of MATE1 and MATE2K transporters, as well as P-gp and BCRP. In conclusion, iruplinalkib, a highly active and selective ALK/ROS1 inhibitor, exhibited strong antitumor effects in vitro and in crizotinib-resistant models.
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Affiliation(s)
- Yingying Yang
- Department of Nonclinical Development, Qilu Pharmaceutical Co., Ltd., Jinan, 250104, China
| | - Qingmei Zheng
- Department of Nonclinical Development, Qilu Pharmaceutical Co., Ltd., Jinan, 250104, China
| | - Xinmei Wang
- Department of Nonclinical Development, Qilu Pharmaceutical Co., Ltd., Jinan, 250104, China
| | - Shuyong Zhao
- Department of Nonclinical Development, Qilu Pharmaceutical Co., Ltd., Jinan, 250104, China
| | - Wenshu Huang
- Department of Nonclinical Development, Qilu Pharmaceutical Co., Ltd., Jinan, 250104, China
| | - Linchao Jia
- Department of Nonclinical Development, Qilu Pharmaceutical Co., Ltd., Jinan, 250104, China
| | - Cuicui Ma
- Department of Nonclinical Development, Qilu Pharmaceutical Co., Ltd., Jinan, 250104, China
| | - Shicong Liu
- Department of Nonclinical Development, Qilu Pharmaceutical Co., Ltd., Jinan, 250104, China
| | - Yongpeng Zhang
- Department of Nonclinical Development, Qilu Pharmaceutical Co., Ltd., Jinan, 250104, China
| | - Qianqian Xin
- Department of Nonclinical Development, Qilu Pharmaceutical Co., Ltd., Jinan, 250104, China
| | - Yan Sun
- Department of Clinical Development, Qilu Pharmaceutical Co., Ltd., Jinan, 250104, China
| | - Shansong Zheng
- Department of Clinical Pharmacology, Qilu Pharmaceutical Co., Ltd., 8888 Lvyou Road, High-tech Zone, Jinan, 250104, China.
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16
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Desai A, Lovly CM. Strategies to overcome resistance to ALK inhibitors in non-small cell lung cancer: a narrative review. Transl Lung Cancer Res 2023; 12:615-628. [PMID: 37057106 PMCID: PMC10087990 DOI: 10.21037/tlcr-22-708] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 02/20/2023] [Indexed: 04/15/2023]
Abstract
Background and Objective Anaplastic lymphoma kinase (ALK) rearrangements are detected in 3-7% of advanced non-small cell lung cancer (NSCLC). There are currently 5 U.S Food and Drug Administration (FDA)-approved ALK tyrosine kinase inhibitors (TKIs) for the treatment of patients with ALK-positive lung cancer in the advanced/metastatic disease setting. Despite these advances, most patients with ALK-positive lung cancer who are treated with ALK TKI therapy ultimately experience disease progression due to various mechanisms of drug resistance. In this review, we discuss strategies to address acquired therapeutic resistance to ALK inhibition, novel agents and combinatorial strategies in development for both on and off-target resistance, and some emerging approaches to prolong response to ALK inhibitors. Methods We performed a search of peer-reviewed literature in the English language, conference abstracts, and trial registrations from the MEDLINE (Ovid), Embase (Elsevier), and CENTRAL (Cochrane Library) databases and major international oncology meetings up to August 2022. We then screened for studies describing interventions to overcome ALK resistance based on review of each title and abstract. Key Content and Findings For patients with oligo-progression, treatment may include maintaining the same systemic treatment beyond progression while adding local therapies to progressing lesions. Strategies to combat ALK TKI resistance mediated by on-target resistance mechanisms include 4th generation TKIs (TPX-0131, NVL-655) and proteolysis-targeting chimeras (PROTACs) currently in development. While for those patients who develop tumor progression due to off-target (ALK independent) resistance, options may include combination therapies targeting ALK and other downstream or parallel pathways, novel antibody drug conjugates, or combinations of ALK inhibitors with chemotherapy and immunotherapy. Lastly, other potential strategies being explored in the clinic include circulating tumor DNA (ctDNA) surveillance to monitor for molecular mediators of drug resistance prior to frank progression on imaging studies and utilization of ALK TKIs in the adjuvant and neoadjuvant settings. Conclusions Strategies to overcome resistance to currently available ALK inhibitors are urgently needed. Given the variety of resistance mechanisms, tailormade approaches are required for disease control.
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Affiliation(s)
- Aakash Desai
- Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | - Christine M. Lovly
- Division of Hematology-Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
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17
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Cheon SY, Kwon S. Molecular Anatomy of the EML4-ALK Fusion Protein for the Development of Novel Anticancer Drugs. Int J Mol Sci 2023; 24:ijms24065821. [PMID: 36982897 PMCID: PMC10054655 DOI: 10.3390/ijms24065821] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 03/15/2023] [Accepted: 03/16/2023] [Indexed: 03/30/2023] Open
Abstract
The EML4 (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) fusion gene in non-small-cell lung cancer (NSCLC) was first identified in 2007. As the EML4-ALK fusion protein promotes carcinogenesis in lung cells, much attention has been paid to it, leading to the development of therapies for patients with NSCLC. These therapies include ALK tyrosine kinase inhibitors and heat shock protein 90 inhibitors. However, detailed information on the entire structure and function of the EML4-ALK protein remains deficient, and there are many obstacles to overcome in the development of novel anticancer agents. In this review, we describe the respective partial structures of EML4 and ALK that are known to date. In addition to their structures, noteworthy structural features and launched inhibitors of the EML4-ALK protein are summarized. Furthermore, based on the structural features and inhibitor-binding modes, we discuss strategies for the development of novel inhibitors targeting the EML4-ALK protein.
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Affiliation(s)
- So Yeong Cheon
- Department of Biotechnology, Konkuk University, Chungju 27478, Republic of Korea
- Research Institute for Biomedical & Health Science, Konkuk University, Chungju 27478, Republic of Korea
| | - Sunghark Kwon
- Department of Biotechnology, Konkuk University, Chungju 27478, Republic of Korea
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18
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Jin H, Wang L, Bernards R. Rational combinations of targeted cancer therapies: background, advances and challenges. Nat Rev Drug Discov 2023; 22:213-234. [PMID: 36509911 DOI: 10.1038/s41573-022-00615-z] [Citation(s) in RCA: 172] [Impact Index Per Article: 86.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/16/2022] [Indexed: 12/15/2022]
Abstract
Over the past two decades, elucidation of the genetic defects that underlie cancer has resulted in a plethora of novel targeted cancer drugs. Although these agents can initially be highly effective, resistance to single-agent therapies remains a major challenge. Combining drugs can help avoid resistance, but the number of possible drug combinations vastly exceeds what can be tested clinically, both financially and in terms of patient availability. Rational drug combinations based on a deep understanding of the underlying molecular mechanisms associated with therapy resistance are potentially powerful in the treatment of cancer. Here, we discuss the mechanisms of resistance to targeted therapies and how effective drug combinations can be identified to combat resistance. The challenges in clinically developing these combinations and future perspectives are considered.
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Affiliation(s)
- Haojie Jin
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Liqin Wang
- Division of Molecular Carcinogenesis, Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands.
| | - René Bernards
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Division of Molecular Carcinogenesis, Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands.
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19
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Schneider JL, Lin JJ, Shaw AT. ALK-positive lung cancer: a moving target. NATURE CANCER 2023; 4:330-343. [PMID: 36797503 PMCID: PMC10754274 DOI: 10.1038/s43018-023-00515-0] [Citation(s) in RCA: 60] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 01/10/2023] [Indexed: 02/18/2023]
Abstract
Anaplastic lymphoma kinase (ALK) is a potent oncogenic driver in lung cancer. ALK tyrosine kinase inhibitors yield significant benefit in patients with ALK fusion-positive (ALK+) lung cancers; yet the durability of response is limited by drug resistance. Elucidation of on-target resistance mechanisms has facilitated the development of next-generation ALK inhibitors, but overcoming ALK-independent resistance mechanisms remains a challenge. In this Review, we discuss the molecular underpinnings of acquired resistance to ALK-directed therapy and highlight new treatment approaches aimed at inducing long-term remission in ALK+ disease.
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Affiliation(s)
- Jaime L Schneider
- Massachusetts General Hospital Cancer Center and Department of Medicine, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Jessica J Lin
- Massachusetts General Hospital Cancer Center and Department of Medicine, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Alice T Shaw
- Massachusetts General Hospital Cancer Center and Department of Medicine, Boston, MA, USA.
- Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
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Wang Z, Xing Y, Li B, Li X, Liu B, Wang Y. Molecular pathways, resistance mechanisms and targeted interventions in non-small-cell lung cancer. MOLECULAR BIOMEDICINE 2022; 3:42. [PMID: 36508072 PMCID: PMC9743956 DOI: 10.1186/s43556-022-00107-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 11/03/2022] [Indexed: 12/14/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related mortality worldwide. The discovery of tyrosine kinase inhibitors effectively targeting EGFR mutations in lung cancer patients in 2004 represented the beginning of the precision medicine era for this refractory disease. This great progress benefits from the identification of driver gene mutations, and after that, conventional and new technologies such as NGS further illustrated part of the complex molecular pathways of NSCLC. More targetable driver gene mutation identification in NSCLC patients greatly promoted the development of targeted therapy and provided great help for patient outcomes including significantly improved survival time and quality of life. Herein, we review the literature and ongoing clinical trials of NSCLC targeted therapy to address the molecular pathways and targeted intervention progress in NSCLC. In addition, the mutations in EGFR gene, ALK rearrangements, and KRAS mutations in the main sections, and the less common molecular alterations in MET, HER2, BRAF, ROS1, RET, and NTRK are discussed. The main resistance mechanisms of each targeted oncogene are highlighted to demonstrate the current dilemma of targeted therapy in NSCLC. Moreover, we discuss potential therapies to overcome the challenges of drug resistance. In this review, we manage to display the current landscape of targetable therapeutic patterns in NSCLC in this era of precision medicine.
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Affiliation(s)
- Zixi Wang
- grid.412901.f0000 0004 1770 1022Thoracic Oncology Ward, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Yurou Xing
- grid.412901.f0000 0004 1770 1022Thoracic Oncology Ward, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Bingjie Li
- grid.412901.f0000 0004 1770 1022Thoracic Oncology Ward, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Xiaoyu Li
- grid.412901.f0000 0004 1770 1022Clinical Trial Center, National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drugs, West China Hospital, Sichuan University, Chengdu, Sichuan China ,grid.412901.f0000 0004 1770 1022State Key Laboratory Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Bin Liu
- grid.54549.390000 0004 0369 4060Department of Medical Oncology, School of Medicine, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, Sichuan China
| | - Yongsheng Wang
- grid.412901.f0000 0004 1770 1022Thoracic Oncology Ward, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan China ,grid.412901.f0000 0004 1770 1022State Key Laboratory Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan China
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Qiu YF, Song LH, Jiang GL, Zhang Z, Liu XY, Wang G. Hallmarks of Anaplastic Lymphoma Kinase Inhibitors with Its Quick Emergence of Drug Resistance. PHARMACEUTICAL FRONTS 2022. [DOI: 10.1055/s-0042-1758542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Anaplastic lymphoma kinase (ALK) is one of the most popular targets for anticancer therapies. In the past decade, the use of anaplastic lymphoma tyrosine kinase inhibitors (ALK-TKIs), including crizotinib and ceritinib, has been a reliable and standard options for patients with lung cancer, particularly for patients with nonsmall cell lung carcinoma. ALK-targeted therapies initially benefit the patients, yet, resistance eventually occurs. Therefore, resistance mechanisms of ALK-TKIs and the solutions have become a formidable challenge in the development of ALK inhibitors. In this review, based on the knowledge of reported ALK inhibitors, we illustrated the crystal structures of ALK, summarized the resistance mechanisms of ALK-targeted drugs, and proposed potential therapeutic strategies to prevent or overcome the resistance.
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Affiliation(s)
- Yong-Fu Qiu
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
| | - Lian-Hua Song
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, People's Republic of China
| | - Gang-Long Jiang
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
| | - Zhen Zhang
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
- School of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, People's Republic of China
| | - Xu-Yan Liu
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
| | - Guan Wang
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
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22
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Bennison SA, Liu X, Toyo-Oka K. Nuak kinase signaling in development and disease of the central nervous system. Cell Signal 2022; 100:110472. [PMID: 36122883 DOI: 10.1016/j.cellsig.2022.110472] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 09/11/2022] [Accepted: 09/13/2022] [Indexed: 01/14/2023]
Abstract
Protein kinases represent important signaling hubs for a variety of biological functions. Many kinases are traditionally studied for their roles in cancer cell biology, but recent advances in neuroscience research show repurposed kinase function to be important for nervous system development and function. Two members of the AMP-activated protein kinase (AMPK) related family, NUAK1 and NUAK2, have drawn attention in neuroscience due to their mutations in autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia, and intellectual disability (ID). Furthermore, Nuak kinases have also been implicated in tauopathy and other disorders of aging. This review highlights what is known about the Nuak kinases in nervous system development and disease and explores the possibility of Nuak kinases as targets for therapeutic innovation.
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Affiliation(s)
- Sarah A Bennison
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA
| | - Xiaonan Liu
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
| | - Kazuhito Toyo-Oka
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
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23
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Ahn MJ, Kim HR, Yang JCH, Han JY, Li JYC, Hochmair MJ, Chang GC, Delmonte A, Lee KH, Campelo RG, Gridelli C, Spira AI, Califano R, Griesinger F, Ghosh S, Felip E, Kim DW, Liu Y, Zhang P, Popat S, Camidge DR. Efficacy and Safety of Brigatinib Compared With Crizotinib in Asian vs. Non-Asian Patients With Locally Advanced or Metastatic ALK-Inhibitor-Naive ALK+ Non-Small Cell Lung Cancer: Final Results From the Phase III ALTA-1L Study. Clin Lung Cancer 2022; 23:720-730. [PMID: 36038416 DOI: 10.1016/j.cllc.2022.07.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/08/2022] [Accepted: 07/16/2022] [Indexed: 01/27/2023]
Abstract
BACKGROUND Brigatinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor with demonstrated efficacy in locally advanced and metastatic non-small cell lung cancer (NSCLC) in crizotinib-refractory and ALK inhibitor-naive settings. This analysis assessed brigatinib in Asian vs. non-Asian patients from the first-line ALTA-1L trial. PATIENTS AND METHODS This was a subgroup analysis from the phase III ALTA-1L trial of brigatinib vs. crizotinib in ALK inhibitor-naive ALK+ NSCLC. The primary endpoint was progression-free survival (PFS) as assessed by blinded independent review committee (BIRC). Secondary endpoints included confirmed objective response rate (ORR) and overall survival (OS) in the overall population and BIRC-assessed intracranial ORR and PFS in patients with brain metastases. RESULTS Of the 275 randomized patients, 108 were Asian. Brigatinib showed consistent superiority in BIRC-assessed PFS vs. crizotinib in Asian (hazard ratio [HR]: 0.35 [95% CI: 0.20-0.59]; log-rank P = .0001; median 24.0 vs. 11.1 months) and non-Asian (HR: 0.56 [95% CI: 0.38-0.84]; log-rank P = .0041; median 24.7 vs. 9.4 months) patients. Results were consistent with investigator-assessed PFS and BIRC-assessed intracranial PFS. Brigatinib was well tolerated. Toxicity profiles and dose modification rates were similar between Asian and non-Asian patients. CONCLUSION Efficacy with brigatinib was consistently better than with crizotinib in Asian and non-Asian patients with locally advanced or metastatic ALK inhibitor-naive ALK-+ NSCLC. There were no clinically notable differences in overall safety in Asian vs. non-Asian patients.
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Affiliation(s)
- Myung J Ahn
- Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
| | - Hye R Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea
| | - James C H Yang
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan, and Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Ji-Yu Han
- Center for Lung Cancer, National Cancer Center, Goyang, South Korea
| | - Jacky Yu-Chung Li
- Department of Clinical Oncology, Hong Kong United Oncology Centre, Kowloon, Hong Kong
| | - Maximilian J Hochmair
- Department of Respiratory and Critical Care Medicine, Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Klinik Floridsdorf, Vienna, Austria
| | - Gee-Chen Chang
- School of Medicine, and Institute of Medicine, Chung Shan Medical University, Division of Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, and Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Angelo Delmonte
- Medical Oncology, Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" (IRST), IRCCS, Meldola, Italy
| | - Ki H Lee
- Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, South Korea
| | - Rosario G Campelo
- Medical Oncology Department, Thoracic Tumors Unit, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain
| | - Cesare Gridelli
- Division of Medical Oncology, A.O.S.G. Moscati, Avellino, Italy
| | - Alexander I Spira
- Medical Oncology, Virginia Cancer Specialists and US Oncology Research, Fairfax, VA
| | - Raffaele Califano
- Department of Medical Oncology, The Christie NHS Foundation Trust, and Division of Cancer Sciences, The University of Manchester, Manchester, England, UK
| | - Frank Griesinger
- University Department of Internal Medicine-Oncology, Pius-Hospital Oldenburg, University of Oldenburg, Oldenburg, Germany
| | - Sharmistha Ghosh
- Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, England, UK
| | - Enriqueta Felip
- Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Dong-Wan Kim
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Republic of Korea
| | - Yuyin Liu
- Oncology Statistics, Takeda Development Center Americas, Inc., Lexington, MA
| | - Pingkuan Zhang
- Clinical Science, Takeda Development Center Americas, Inc., Lexington, MA
| | - Sanjay Popat
- Lung Unit, The Royal Marsden Hospital and The Institute of Cancer Research, London, England, UK
| | - D Ross Camidge
- Department of Medicine, Division of Medical Oncology, University of Colorado Cancer Center, Aurora, CO
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24
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Xie B, Qiu Y, Zhou J, Du D, Ma H, Ji J, Zhu L, Zhang W. Establishment of an acquired lorlatinib-resistant cell line of non-small cell lung cancer and its mediated resistance mechanism. Clin Transl Oncol 2022; 24:2231-2240. [PMID: 35852680 DOI: 10.1007/s12094-022-02884-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 06/27/2022] [Indexed: 10/17/2022]
Abstract
PURPOSE Although lorlatinib, the third generation of echinoderm microtubule protein 4-anaplastic lymphoma kinase (EML4-ALK) tyrosine kinase inhibitor (TKI), overcame the previous generation ALK-TKIs' drug resistance problems, but the mechanism of lorlatinib resistance remained unclear. Furthermore, optimal chemotherapy for lorlatinib-resistant non-small cell lung cancer (NSCLC) patients was still unknown. METHODS A lorlatinib-resistant NSCLC cell line SNU-2535LR was generated by gradually increasing dose of lorlatinib to crizotinib-resistant cell line SNU-2535 in vitro. To study the resistance mechanism of SNU-2535LR cells, we applied CCK-8 assay to detect the sensitivity of crizotinib and the reverse effect of APR-246, a p53 activator, on lorlatinib-induced resistance and different chemotherapy drugs to SNU-2535LR cells. We also detected the expressions of EML4-ALK-related proteins of SNU-2535LR cells via western blot.Please confirm that author names have been identified correctly and are presented in the right order.Dear Editor: I have carefully confirmed that the author names have been identified correctly and are presented in right order.Thank you very much! Your sincerely BoXie RESULTS: The sensitivity of SNU-2535LR cells to lorlatinib was decreased significantly than that of SNU-2535 cells. EML4-ALK fusion was decreased both at protein level and DNA level in SNU-2535LR cells. More interesting, the crizotinib-resistant mutation ALK p.G1269A disappeared, while new TP53 mutation emerged in SNU-2535LR cells. APR-246 can reverse the lorlatinib resistance in SNU-2535LR cells, with a reversal index of 4.768. Compared with SNU-2535 cells, the sensitivity of SNU-2535LR cells to gemcitabine, docetaxel and paclitaxel was significantly increased (P < 0.05), but decreased to cisplatin (P < 0.05). CONCLUSION This study demonstrated that the combination of p53 protein agonist and lorlatinib may provide a new therapeutic strategy for NSCLC patients with lorlatinib resistance and TP53 mutation. Furthermore, the results also provide guidance for selecting optimal chemo-regimens for NSCLC patients after ALK-TKIs failure.
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Affiliation(s)
- Bo Xie
- Department of Oncology, General Hospital of Southern Theater Command, PLA, No.111, Liuhua Rd., Guangzhou, 510010, China
| | - Ying Qiu
- Department of Oncology, General Hospital of Southern Theater Command, PLA, No.111, Liuhua Rd., Guangzhou, 510010, China
| | - Juan Zhou
- Department of Oncology, General Hospital of Southern Theater Command, PLA, No.111, Liuhua Rd., Guangzhou, 510010, China
| | - Dou Du
- Department of Oncology, General Hospital of Southern Theater Command, PLA, No.111, Liuhua Rd., Guangzhou, 510010, China
| | - Haochuan Ma
- Department of Oncology, General Hospital of Southern Theater Command, PLA, No.111, Liuhua Rd., Guangzhou, 510010, China
| | - Jiapeng Ji
- Department of Oncology, General Hospital of Southern Theater Command, PLA, No.111, Liuhua Rd., Guangzhou, 510010, China
| | - Liquan Zhu
- Department of Oncology, General Hospital of Southern Theater Command, PLA, No.111, Liuhua Rd., Guangzhou, 510010, China
| | - Weimin Zhang
- Department of Oncology, General Hospital of Southern Theater Command, PLA, No.111, Liuhua Rd., Guangzhou, 510010, China.
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25
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Wiedemann C, Kazdal D, Cvetkovic J, Kunz J, Fisch D, Kirchner M, Kriegsmann M, Sültmann H, Heussel CP, Bischoff H, Thomas M, Stenzinger A, Christopoulos P. Lorlatinib and compound mutations in ALK+ large-cell neuroendocrine lung carcinoma: a case report. Cold Spring Harb Mol Case Stud 2022; 8:mcs.a006234. [PMID: 36207130 PMCID: PMC9632356 DOI: 10.1101/mcs.a006234] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 10/05/2022] [Indexed: 01/31/2023] Open
Abstract
Large-cell neuroendocrine lung carcinoma (LCNEC) is a high-grade neoplasm with median survival of 1 year and limited therapeutic options. Here, we report the unusual case of a 47-yr-old female smoker with stage IV LCNEC featuring EML4-ALK variant 2 (E20:A20), wild-type TP53/RB1, and low tumor mutational burden of 3.91 mut/Mb. Despite early progression within 3 mo under crizotinib, a durable response was achieved with alectinib. Oligoprogression in the left breast 10 mo later was treated by surgery, followed by a switch to ceritinib upon multifocal progression and detection of ALK:p.V1180L in the mastectomy specimen, but without success. Another rebiopsy revealed ALK:p.L1196M, but the tumor did not respond to brigatinib or carboplatin/pemetrexed, before stabilization under lorlatinib. Diffuse progression 8 mo later with detection of ALK :p.L1196M/p.G1202R and p.L1196M/ p.D1203N evolving from the previous p.L1196M did not respond to chemoimmunotherapy, and the patient succumbed with an overall survival (OS) of 37 mo. This case illustrates the importance of molecular profiling for LCNEC regardless of smoking status, and the superiority of next-generation ALK inhibitors compared to crizotinib for ALK+ cases. Lorlatinib retained efficacy in the heavily pretreated setting, whereas its upfront use could possibly have prevented the stepwise emergence of compound ALK mutations. Furthermore, the disease course was more aggressive and OS shorter compared to the V2/TP53wt ALK+ lung adenocarcinoma, whereas crizotinib, ceritinib, and brigatinib did not confer the benefit expected according to next-generation sequencing results, which also underline the need for more potent drugs against ALK in the high-risk setting of neuroendocrine histology.
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Affiliation(s)
- Christiane Wiedemann
- Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital and National Center for Tumor Diseases, Heidelberg, 69126 Germany
| | - Daniel Kazdal
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, 69120 Germany;,Translational Lung Research Center Heidelberg (TLRC-H), member of the German Center for Lung Research (DZL), Heidelberg, 69120 Germany
| | - Jelena Cvetkovic
- Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital and National Center for Tumor Diseases, Heidelberg, 69126 Germany
| | - Julia Kunz
- Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital and National Center for Tumor Diseases, Heidelberg, 69126 Germany
| | - David Fisch
- Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital and National Center for Tumor Diseases, Heidelberg, 69126 Germany
| | - Martina Kirchner
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, 69120 Germany
| | - Mark Kriegsmann
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, 69120 Germany;,Translational Lung Research Center Heidelberg (TLRC-H), member of the German Center for Lung Research (DZL), Heidelberg, 69120 Germany
| | - Holger Sültmann
- Translational Lung Research Center Heidelberg (TLRC-H), member of the German Center for Lung Research (DZL), Heidelberg, 69120 Germany;,Division of Cancer Genome Research, German Cancer Research Center (DKFZ), Heidelberg, 69120 Germany
| | - Claus-Peter Heussel
- Translational Lung Research Center Heidelberg (TLRC-H), member of the German Center for Lung Research (DZL), Heidelberg, 69120 Germany;,Department of Radiology with Nuclear Medicine, Thoraxklinik at Heidelberg University Hospital, Heidelberg, 69126 Germany
| | - Helge Bischoff
- Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital and National Center for Tumor Diseases, Heidelberg, 69126 Germany
| | - Michael Thomas
- Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital and National Center for Tumor Diseases, Heidelberg, 69126 Germany;,Translational Lung Research Center Heidelberg (TLRC-H), member of the German Center for Lung Research (DZL), Heidelberg, 69120 Germany
| | - Albrecht Stenzinger
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, 69120 Germany;,Translational Lung Research Center Heidelberg (TLRC-H), member of the German Center for Lung Research (DZL), Heidelberg, 69120 Germany
| | - Petros Christopoulos
- Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital and National Center for Tumor Diseases, Heidelberg, 69126 Germany;,Translational Lung Research Center Heidelberg (TLRC-H), member of the German Center for Lung Research (DZL), Heidelberg, 69120 Germany
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26
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A kinase inhibitor screen reveals MEK1/2 as a novel therapeutic target to antagonize IGF1R-mediated antiestrogen resistance in ERα-positive luminal breast cancer. Biochem Pharmacol 2022; 204:115233. [PMID: 36041543 DOI: 10.1016/j.bcp.2022.115233] [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: 06/10/2022] [Revised: 08/19/2022] [Accepted: 08/22/2022] [Indexed: 11/23/2022]
Abstract
Antiestrogen resistance of breast cancer has been related to enhanced growth factor receptor expression and activation. We have previously shown that ectopic expression and subsequent activation of the insulin-like growth factor-1 receptor (IGF1R) or the epidermal growth factor receptor (EGFR) in MCF7 or T47D breast cancer cells results in antiestrogen resistance. In order to identify novel therapeutic targets to prevent this antiestrogen resistance, we performed kinase inhibitor screens with 273 different inhibitors in MCF7 cells overexpressing IGF1R or EGFR. Kinase inhibitors that antagonized antiestrogen resistance but are not directly involved in IGF1R or EGFR signaling were prioritized for further analyses. Various ALK (anaplastic lymphoma receptor tyrosine kinase) inhibitors inhibited cell proliferation in IGF1R expressing cells under normal and antiestrogen resistance conditions by preventing IGF1R activation and subsequent downstream signaling; the ALK inhibitors did not affect EGFR signaling. On the other hand, MEK (mitogen-activated protein kinase kinase)1/2 inhibitors, including PD0325901, selumetinib, trametinib and TAK733, selectively antagonized IGF1R signaling-mediated antiestrogen resistance but did not affect cell proliferation under normal growth conditions. RNAseq analysis revealed that MEK inhibitors PD0325901 and selumetinib drastically altered cell cycle progression and cell migration networks under IGF1R signaling-mediated antiestrogen resistance. In a group of 219 patients with metastasized ER+ breast cancer, strong pMEK staining showed a significant correlation with no clinical benefit of first-line tamoxifen treatment. We propose a critical role for MEK activation in IGF1R signaling-mediated antiestrogen resistance and anticipate that dual-targeted therapy with a MEK inhibitor and antiestrogen could improve treatment outcome.
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27
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Sakashita T, Yanagitani N, Koike S, Low SK, Takagi S, Baba S, Takeuchi K, Nishio M, Fujita N, Katayama R. Fibroblast growth factor receptor 3 overexpression mediates ALK inhibitor resistance in ALK-rearranged non-small cell lung cancer. Cancer Sci 2022; 113:3888-3900. [PMID: 35950895 PMCID: PMC9633314 DOI: 10.1111/cas.15529] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/14/2022] [Accepted: 07/29/2022] [Indexed: 11/28/2022] Open
Abstract
The rearrangement of anaplastic lymphoma kinase (ALK) occurs in 3%‐5% of patients with non–small cell lung cancer (NSCLC) and confers sensitivity to ALK–tyrosine kinase inhibitors (TKIs). For the treatment of patients with ALK‐rearranged NSCLC, various additional ALK‐TKIs have been developed. Ceritinib is a second‐generation ALK‐TKI and has shown great efficacy in the treatment of patients with both newly diagnosed and crizotinib (a first‐generation ALK‐TKI)‐refractory ALK‐rearranged NSCLC. However, tumors can also develop ceritinib resistance. This may result from secondary ALK mutations, but other mechanisms responsible for this have not been fully elucidated. In this study, we explored the mechanisms of ceritinib resistance by establishing ceritinib‐resistant, echinoderm microtubule‐associated protein‐like 4 (EML4)‐ALK–positive H3122 cells and ceritinib‐resistant patient‐derived cells. We identified a mechanism of ceritinib resistance induced by bypass signals that is mediated by the overexpression and activation of fibroblast growth factor receptor 3 (FGFR3). FGFR3 knockdown by small hairpin RNA or treatment with FGFR inhibitors was found to resensitize the resistant cells to ceritinib in vitro and in vivo. FGFR ligands from either human serum or fetal bovine serum were able to activate FGFR3 and induce ceritinib resistance. A detailed analysis of ceritinib‐resistant patient‐derived specimens confirmed that tyrosine‐protein kinase Met (cMET) amplification induces ceritinib resistance. Amplified cMET counteractivated EGFR and/or Her3 and induced ceritinib resistance. These results reveal multiple ceritinib resistance mechanisms and suggest that ceritinib resistance might be overcome by identifying precise resistance mechanisms.
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Affiliation(s)
- Takuya Sakashita
- Div. of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, JAPAN.,Department of Computational Biology and Medical Science, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, JAPAN.,AstraZeneca K.K., Osaka, JAPAN
| | - Noriko Yanagitani
- Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, JAPAN
| | - Sumie Koike
- Div. of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, JAPAN
| | - Siew-Kee Low
- Cancer Precision Medicine Center, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Satoshi Takagi
- Div. of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, JAPAN
| | - Satoko Baba
- Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.,Pathology Project for Molecular Targets, the Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, JAPAN
| | - Kengo Takeuchi
- Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.,Pathology Project for Molecular Targets, the Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, JAPAN.,Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Makoto Nishio
- Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, JAPAN
| | - Naoya Fujita
- Director, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, JAPAN
| | - Ryohei Katayama
- Div. of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, JAPAN.,Department of Computational Biology and Medical Science, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, JAPAN
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28
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Itchins M, Pavlakis N. The quantum leap in therapeutics for advanced ALK+ non-small cell lung cancer and pursuit to cure with precision medicine. Front Oncol 2022; 12:959637. [PMID: 36003760 PMCID: PMC9393505 DOI: 10.3389/fonc.2022.959637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 07/08/2022] [Indexed: 11/13/2022] Open
Abstract
Since the discovery 15 years ago, we have seen a quantum leap in the treatment and survival for individuals diagnosed with ALK+ lung cancers. Unfortunately however, for most, the diagnosis is made in an incurable circumstance given the late presentation of symptoms. Through a revolutionary wave of therapeutics, individuals may remarkably live over a decade, however many fall short of this milestone, as the molecular profile of this disease is very heterogeneous, reflected in variable survival outcomes. Despite a significant improval in survival and quality of life with ALK-inhibitor monotherapies, now available across multiple-generations, drug resistance and disease relapse remains inevitable, and treatment is offered in an empiric, stepwise, non personalised biomarker informed fashion. A proposed future focus to treating ALK to improve the chronicity of this disease and even promote cure, is to deliver a personalised dynamic approach to care, with rational combinations of drugs in conjunction with local ablative therapies to prevent and constantly proactively alter clonal selection. Such an approach would be informed by precision imaging with MRI-brain and FDG-PETs sequentially, and by regular plasma sampling including for circulating tumour DNA sequencing with personalised therapeutic switches occurring prior to the emergence of radiological and clinical relapse. Such an approach to care will require a complete paradigm shift in the way we approach the treatment of advanced cancer, however evidence to date in ALK+ lung cancers, support this new frontier of investigation.
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Affiliation(s)
- Malinda Itchins
- Department of Medical Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, St Leonards, NSW, Australia
- Northern Clinical School, University of Sydney, Kolling Institute, St Leonards, NSW, Australia
- North Shore Health Hub, GenesisCare, St Leonards, NSW, Australia
- *Correspondence: Malinda Itchins,
| | - Nick Pavlakis
- Department of Medical Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, St Leonards, NSW, Australia
- Northern Clinical School, University of Sydney, Kolling Institute, St Leonards, NSW, Australia
- North Shore Health Hub, GenesisCare, St Leonards, NSW, Australia
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29
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Jawarkar RD, Sharma P, Jain N, Gandhi A, Mukerjee N, Al-Mutairi AA, Zaki MEA, Al-Hussain SA, Samad A, Masand VH, Ghosh A, Bakal RL. QSAR, Molecular Docking, MD Simulation and MMGBSA Calculations Approaches to Recognize Concealed Pharmacophoric Features Requisite for the Optimization of ALK Tyrosine Kinase Inhibitors as Anticancer Leads. Molecules 2022; 27:molecules27154951. [PMID: 35956900 PMCID: PMC9370430 DOI: 10.3390/molecules27154951] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/15/2022] [Accepted: 07/22/2022] [Indexed: 12/04/2022] Open
Abstract
ALK tyrosine kinase ALK TK is an important target in the development of anticancer drugs. In the present work, we have performed a QSAR analysis on a dataset of 224 molecules in order to quickly predict anticancer activity on query compounds. Double cross validation assigns an upward plunge to the genetic algorithm−multi linear regression (GA-MLR) based on robust univariate and multivariate QSAR models with high statistical performance reflected in various parameters like, fitting parameters; R2 = 0.69−0.87, F = 403.46−292.11, etc., internal validation parameters; Q2LOO = 0.69−0.86, Q2LMO = 0.69−0.86, CCCcv = 0.82−0.93, etc., or external validation parameters Q2F1 = 0.64−0.82, Q2F2 = 0.63−0.82, Q2F3 = 0.65−0.81, R2ext = 0.65−0.83 including RMSEtr < RMSEcv. The present QSAR evaluation successfully identified certain distinct structural features responsible for ALK TK inhibitory potency, such as planar Nitrogen within four bonds from the Nitrogen atom, Fluorine atom within five bonds beside the non-ring Oxygen atom, lipophilic atoms within two bonds from the ring Carbon atoms. Molecular docking, MD simulation, and MMGBSA computation results are in consensus with and complementary to the QSAR evaluations. As a result, the current study assists medicinal chemists in prioritizing compounds for experimental detection of anticancer activity, as well as their optimization towards more potent ALK tyrosine kinase inhibitor.
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Affiliation(s)
- Rahul D. Jawarkar
- Faculty of Pharmacy, Oriental University, Indore 453555, Madhya Pradesh, India; (P.S.); (N.J.)
- Correspondence: (R.D.J.); (M.E.A.Z.); Tel.: +91-7385178762 (R.D.J.)
| | - Praveen Sharma
- Faculty of Pharmacy, Oriental University, Indore 453555, Madhya Pradesh, India; (P.S.); (N.J.)
| | - Neetesh Jain
- Faculty of Pharmacy, Oriental University, Indore 453555, Madhya Pradesh, India; (P.S.); (N.J.)
| | - Ajaykumar Gandhi
- Department of Chemistry, Government College of Arts and Science, Aurangabad 431004, Maharashtra, India;
| | - Nobendu Mukerjee
- Department of Microbiology, Ramakrishna Mission Vivekananda Centenary College, Kolkata 700118, West Bengal, India;
| | - Aamal A. Al-Mutairi
- Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh 13318, Saudi Arabia; (A.A.A.-M.); (S.A.A.-H.)
| | - Magdi E. A. Zaki
- Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh 13318, Saudi Arabia; (A.A.A.-M.); (S.A.A.-H.)
- Correspondence: (R.D.J.); (M.E.A.Z.); Tel.: +91-7385178762 (R.D.J.)
| | - Sami A. Al-Hussain
- Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh 13318, Saudi Arabia; (A.A.A.-M.); (S.A.A.-H.)
| | - Abdul Samad
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tishk International University, Erbil 44001, Kurdistan Region, Iraq;
| | - Vijay H. Masand
- Department of Chemistry, Vidyabharati Mahavidyalalya, Camp Road, Amravati 444602, Maharashtra, India;
| | - Arabinda Ghosh
- Microbiology Division, Department of Botany, Gauhati University, Guwahati 781014, Assam, India;
| | - Ravindra L. Bakal
- Department of Medicinal Chemistry, Dr. Rajendra Gode Institute of Pharmacy, University-Mardi Road, Amravati 444603, Maharashtra, India;
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Cancer: A pathologist's journey from morphology to molecular. Med J Armed Forces India 2022; 78:255-263. [DOI: 10.1016/j.mjafi.2022.06.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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Yang J, Ma D, Liu S, Tan Z, Guo M, Cao Z, Zhang J, Zhai X. Design, synthesis and antitumor evaluation of ATP dual-mimic 2,4-diarylaminopyrimidine and aminoindazole conjugates as potent anaplastic lymphoma kinase inhibitors. Eur J Med Chem 2022; 241:114626. [DOI: 10.1016/j.ejmech.2022.114626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 07/12/2022] [Accepted: 07/21/2022] [Indexed: 11/04/2022]
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Integrating mutational and nonmutational mechanisms of acquired therapy resistance within the Darwinian paradigm. Trends Cancer 2022; 8:456-466. [DOI: 10.1016/j.trecan.2022.02.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/11/2022] [Accepted: 02/14/2022] [Indexed: 02/07/2023]
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Gupta N, Reckamp KL, Camidge DR, Kleijn HJ, Ouerdani A, Bellanti F, Maringwa J, Hanley MJ, Wang S, Zhang P, Venkatakrishnan K. Population Pharmacokinetic and Exposure-Response Analyses From ALTA-1L: Model-Based Analyses Supporting the Brigatinib Dose in ALK-Positive NSCLC. Clin Transl Sci 2022; 15:1143-1154. [PMID: 35041775 PMCID: PMC9099121 DOI: 10.1111/cts.13231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 12/02/2021] [Accepted: 12/24/2021] [Indexed: 11/29/2022] Open
Abstract
The ALK in Lung Cancer Trial of brigAtinib in 1st Line (ALTA-1L) compared brigatinib versus crizotinib in ALK inhibitor-naive patients with ALK+ NSCLC. A population pharmacokinetic (PK) model was used to estimate brigatinib exposures for exposure-efficacy and exposure-safety analyses in ALTA-1L. A previously developed population PK model for brigatinib was applied to estimate brigatinib PK parameters. Relationships between static (time-independent) and dynamic (time-varying) exposure metrics and efficacy (progression-free survival [PFS], objective response rate [ORR], and intracranial ORR) and safety outcomes (selected grade ≥ 2 and grade ≥ 3 adverse events) were evaluated using logistic regression and time-to-event analyses. There were no meaningful differences in brigatinib PK in the first-line and second-line settings, supporting use of the previous population PK model for the first-line population. Exposure-response analyses showed no significant effect of time-varying brigatinib exposure on PFS. Brigatinib exposure was not significantly related to ORR, but higher exposure was associated with higher intracranial ORR (odds ratio: 1.13; 95% confidence interval: 1.01-1.28; P = 0.049). Across the observed median exposure (5th-95th percentile) at steady state for 180 mg once daily, the predicted probability of intracranial ORR was 0.83 (0.58-0.99). Adverse events significantly associated with higher exposure were elevated lipase (grade ≥ 3) and amylase (grade ≥ 2). Time to first brigatinib dose reduction was not related to exposure. These results support the benefit-risk profile of first-line brigatinib 180 mg once daily (7-day lead-in dose at 90 mg once daily) in patients with ALK+ NSCLC.
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Affiliation(s)
- Neeraj Gupta
- Takeda Development Center Americas, Inc., Lexington, MA, USA
| | - Karen L Reckamp
- Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | | | | | | | | | | | | | - Shining Wang
- Takeda Development Center Americas, Inc., Lexington, MA, USA
| | - Pingkuan Zhang
- Takeda Development Center Americas, Inc., Lexington, MA, USA
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Koga T, Suda K, Mitsudomi T. Utility of the Ba/F3 cell system for exploring on-target mechanisms of resistance to targeted therapies for lung cancer. Cancer Sci 2022; 113:815-827. [PMID: 34997674 PMCID: PMC8898722 DOI: 10.1111/cas.15263] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 12/03/2021] [Accepted: 12/12/2021] [Indexed: 11/30/2022] Open
Abstract
Molecular targeted therapies are the standard of care for front‐line treatment of metastatic non‐small‐cell lung cancers (NSCLCs) harboring driver gene mutations. However, despite the initial dramatic responses, the emergence of acquired resistance is inevitable. Acquisition of secondary mutations in the target gene (on‐target resistance) is one of the major mechanisms of resistance. The mouse pro‐B cell line Ba/F3 is dependent on interleukin‐3 for survival and proliferation. Upon transduction of a driver gene, Ba/F3 cells become independent of interleukin‐3 but dependent on the transduced driver gene. Therefore, the Ba/F3 cell line has been a popular system to generate models with oncogene dependence and vulnerability to specific targeted therapies. These models have been used to estimate oncogenicity of driver mutations or efficacies of molecularly targeted drugs. In addition, Ba/F3 models, together with N‐ethyl‐N‐nitrosourea mutagenesis, have been used to derive acquired resistant cells to investigate on‐target resistance mechanisms. Here, we reviewed studies that used Ba/F3 models with EGFR mutations, ALK/ROS1/NTRK/RET fusions, MET exon 14 skipping mutations, or KRAS G12C mutations to investigate secondary/tertiary drug resistant mutations. We determined that 68% of resistance mutations reproducibly detected in clinical cases were also found in Ba/F3 models. In addition, sensitivity data generated with Ba/F3 models correlated well with clinical responses to each drug. Ba/F3 models are useful to comprehensively identify potential mutations that induce resistance to molecularly targeted drugs and to explore drugs to overcome the resistance.
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Affiliation(s)
- Takamasa Koga
- Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Kenichi Suda
- Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Tetsuya Mitsudomi
- Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
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Moskovitz M, Dudnik E, Shamai S, Rotenberg Y, Popovich-Hadari N, Wollner M, Zer A, Gottfried M, Mishaeli M, Rosenberg SK, Onn A, Merimsky O, Urban D, Peled N, Maimon N, Bar J. OUP accepted manuscript. Oncologist 2022; 27:e76-e84. [PMID: 35305096 PMCID: PMC8842297 DOI: 10.1093/oncolo/oyab005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 12/04/2021] [Indexed: 11/12/2022] Open
Abstract
Objectives ALK inhibitors (ALKi) are the standard-of-care treatment for metastatic ALK-rearranged non-small cell lung cancer (NSCLC) in the first- and second-line setting. We conducted a real-world multi-institutional analysis, aiming to compare the efficacy of third-line ALKi versus chemotherapy in these patients. Methods Consecutive ALK-positive metastatic NSCLC patients treated with at least one ALKi were identified in the working databases of 7 Israeli oncology centers (the full cohort). Demographic and clinical data were collected. Patients receiving any systemic treatment beyond 2 ALKi comprised the third-line cohort, whether a third ALKi (group A) or chemotherapy (group B). Groups A and B were compared in terms of overall survival (OS) and time-to-next-treatment line (TNT). Results At a median follow-up of 41 months (95% confidence interval [CI]: 32-55), 80 (47.1%) have died. Median OS (mOS) in the full cohort (n = 170) was 52 months (95% CI: 32-65). Number of ALKi (hazard ratio [HR] 0.765; 95% CI: 0.61-0.95; P = .024) and age (HR 1.02, 95% CI: 1.01-1.04, P = .009) significantly associated with OS in the full cohort. The third-line cohort included 40 patients, of which 27 were treated with third ALKi (group A) and 13 treated with chemotherapy (group B). mOS from third-line initiation was 27 months in group A (95% CI: 13-NR) and 13 months for group B (95% CI: 3-NR); the difference was not significant (NS; P = .12). Chemotherapy as first line (HR 0.17, 95% CI: 0.05-0.52, P = .002) and a higher number of ALKi (HR 0.38, 95% CI: 0.20-0.86, P = .011) associated significantly with longer OS of the third-line cohort. TNT was 10 months for group A (95% CI: 5-19) and 3 months for group B (95% CI: 0-NR); the difference was NS (P = .079). Conclusion We report mature real-world data of more than 4-year mOS in ALK-positive patients. The number of ALKi given was associated with a better outcome. OS and TNT demonstrated a statistically nonsignificant trend for a better outcome in patients receiving a third-line ALKi.
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Affiliation(s)
| | | | - Sivan Shamai
- Oncology Division, Tel Aviv Sourasky Medical Center, Affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yakir Rotenberg
- Sharett Oncology Institute, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | | | - Mira Wollner
- Thoracic Cancer Service, Rambam Health Care Campus, Haifa, Israel
| | - Alona Zer
- Thoracic Cancer Service, Davidoff Cancer Center, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel
| | - Maya Gottfried
- Department of Oncology, Meir Medical Center, Kfar-Saba, Israel
| | - Moshe Mishaeli
- Department of Oncology, Meir Medical Center, Kfar-Saba, Israel
| | | | - Amir Onn
- Thoracic Oncology Service, Institute of Oncology, Sheba Medical Center, Tel HaShomer, Ramat Gan, Israel
| | - Ofer Merimsky
- Oncology Division, Tel Aviv Sourasky Medical Center, Affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Damien Urban
- Thoracic Oncology Service, Institute of Oncology, Sheba Medical Center, Tel HaShomer, Ramat Gan, Israel
| | - Nir Peled
- Present address: The Legacy Heritage Oncology Center, Soroka Medical Center, Beer-Sheva1, Israel
| | | | - Jair Bar
- Corresponding author: Jair Bar, MD, PhD, Institute of Oncology, Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, 5262000-Chair, Israel Lung Cancer Group, Israel. Tel: 972-3530-7096; Fax 972-3530-7097;
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Cheng Y, Zhang T, Xu Q. Therapeutic advances in non-small cell lung cancer: Focus on clinical development of targeted therapy and immunotherapy. MedComm (Beijing) 2021; 2:692-729. [PMID: 34977873 PMCID: PMC8706764 DOI: 10.1002/mco2.105] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 11/20/2021] [Accepted: 11/22/2021] [Indexed: 02/05/2023] Open
Abstract
Lung cancer still contributes to nearly one-quarter cancer-related deaths in the past decades, despite the rapid development of targeted therapy and immunotherapy in non-small cell lung cancer (NSCLC). The development and availability of comprehensive genomic profiling make the classification of NSCLC more precise and personalized. Most treatment decisions of advanced-stage NSCLC have been made based on the genetic features and PD-L1 expression of patients. For the past 2 years, more than 10 therapeutic strategies have been approved as first-line treatment for certain subgroups of NSCLC. However, some major challenges remain, including drug resistance and low rate of overall survival. Therefore, we discuss and review the therapeutic strategies of NSCLC, and focus on the development of targeted therapy and immunotherapy in advanced-stage NSCLC. Based on the latest guidelines, we provide an updated summary on the standard treatment for NSCLC. At last, we discussed several potential therapies for NSCLC. The development of new drugs and combination therapies both provide promising therapeutic effects on NSCLC.
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Affiliation(s)
- Yuan Cheng
- Laboratory of Aging Research and Cancer Drug TargetState Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduChina
| | - Tao Zhang
- Laboratory of Aging Research and Cancer Drug TargetState Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduChina
| | - Qing Xu
- Department of OncologyShanghai Tenth People's HospitalTongji University School of MedicineShanghaiChina
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Resistance to Targeted Agents Used to Treat Paediatric ALK-Positive ALCL. Cancers (Basel) 2021; 13:cancers13236003. [PMID: 34885113 PMCID: PMC8656581 DOI: 10.3390/cancers13236003] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/25/2021] [Accepted: 11/25/2021] [Indexed: 12/25/2022] Open
Abstract
Simple Summary In general, the non-Hodgkin lymphoma (NHL), anaplastic large cell lymphoma (ALCL) diagnosed in childhood has a good survival outcome when treated with multi-agent chemotherapy. However, side effects of treatment are common, and outcomes are poorer after relapse, which occurs in up to 30% of cases. New drugs are required that are more effective and have fewer side effects. Targeted therapies are potential solutions to these problems, however, the development of resistance may limit their impact. This review summarises the potential resistance mechanisms to these targeted therapies. Abstract Non-Hodgkin lymphoma (NHL) is the third most common malignancy diagnosed in children. The vast majority of paediatric NHL are either Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), anaplastic large cell lymphoma (ALCL), or lymphoblastic lymphoma (LL). Multi-agent chemotherapy is used to treat all of these types of NHL, and survival is over 90% but the chemotherapy regimens are intensive, and outcomes are generally poor if relapse occurs. Therefore, targeted therapies are of interest as potential solutions to these problems. However, the major problem with all targeted agents is the development of resistance. Mechanisms of resistance are not well understood, but increased knowledge will facilitate optimal management strategies through improving our understanding of when to select each targeted agent, and when a combinatorial approach may be helpful. This review summarises currently available knowledge regarding resistance to targeted therapies used in paediatric anaplastic lymphoma kinase (ALK)-positive ALCL. Specifically, we outline where gaps in knowledge exist, and further investigation is required in order to find a solution to the clinical problem of drug resistance in ALCL.
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Shen J, Shi H, Zhao Y, Fent K, Zhang K. Large-Scale Transcriptional Profiling of Molecular Perturbations Reveals Cell Line Specific Responses and Implications for Environmental Screening. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2021; 55:15266-15275. [PMID: 34714046 DOI: 10.1021/acs.est.1c04965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Cell-based bioassays represent nearly half of all high-throughput screens currently conducted for risk assessment of environmental chemicals. However, there has long been a concern about the sensitivity and heterogeneity among cell lines, which were explored only in a limited manner. Here, we address this question by conducting a large-scale transcriptome analysis of the responses of discrete cell lines to specific molecules. We report the collections of >223 300 gene expression profiles from a wide array of cell lines exposed to 2243 compounds. Our results demonstrate distinct responses among cell lines at both the gene and the pathway levels. Temporal variations for a very large proportion of compounds occur as well. High sensitivity and/or heterogeneity is either cell line-specific or universal depending on the modes of action of the compounds. Among 12 representative pathways analyzed, distinct cell-chemical interactions exist. On one hand, lung carcinoma cells are always best suited for glucocorticoid receptor agonist identification, while on the other hand, high sensitivity and heterogenic features are universal for histone deacetylase inhibitors and ATPase inhibitors. Our data provide novel insights into the understanding of cell-specific responses and interactions between cells and xenobiotics. The findings have substantial implications for the design, execution, and interpretation of high-throughput screening assays in (eco)toxicology.
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Affiliation(s)
- Jing Shen
- State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, School of Environmental Science and Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Haochun Shi
- State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, School of Environmental Science and Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Yanbin Zhao
- State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, School of Environmental Science and Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Karl Fent
- Institute of Biogeochemistry and Pollution Dynamics, Department of Environmental Systems Science, ETH Zürich, CH-8092 Zürich, Switzerland
| | - Kun Zhang
- State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, School of Environmental Science and Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
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Zhang M, Wang Q, Ke Z, Liu Y, Guo H, Fang S, Lu K. LINC01001 Promotes Progression of Crizotinib-Resistant NSCLC by Modulating IGF2BP2/MYC Axis. Front Pharmacol 2021; 12:759267. [PMID: 34630126 PMCID: PMC8497803 DOI: 10.3389/fphar.2021.759267] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 09/08/2021] [Indexed: 12/25/2022] Open
Abstract
Background: Crizotinib is a microtubule-related protein-4-anaplastic lymphoma kinase (EML4-ALK) multi-target tyrosine kinase inhibitor applied in the treatment of ALK-rearranged NSCLC. However, the specific molecular mechanism underlying its therapeutic effect remains unclear. Therefore, the purpose of this research is to explore the mechanism by which crizotinib targets NSCLC with ALK-rearrangement, mainly whether it is related to LINC01001 in regulating NSCLC progression via IGF2BP2/MYC axis. Methods: RT-qPCR is conducted to evaluate the mRNA levels of LINC01001, IGF2BP2 and MYC in A549/R and H1299/R cells. CCK-8 and EdU assays are performed to assess the viability and proliferation of A549/R and H1299/R cells. Western blot is conducted to measure the levels of PCNA and Ki-67 proteins in A549/R and H1299/R cells. FACs and TUNEL are performed to detect apoptosis of A549/R and H1299/R cells. Immunohistochemical staining is performed to assess the levels of Ki67 in crizotinib-resistant NSCLC tissue. Bioinformatics analysis of multiple CLIP (crosslinking-immunoprecipitation) data found potential binding sites between LINC01001 and IGF2BP2, IGF2BP2 and MYC, that are confirmed by RIP assay and RNA pulldown assay. Results: Our findings illustrated that LINC01001 is highly expressed in crizotinib-resistant NSCLC cells and associated with poor overall survival of NSCLC patients. Inhibition of LINC01001 depresses crizotinib resistance of NSCLC cells. LINC01001 interacts with IGF2BP2, and inhibition of IGF2BP2 depresses crizotinib resistance of NSCLC cells. IGF2BP2 interacts with the mRNA of MYC, and LINC01001 overexpression increases crizotinib resistance of NSCLC via MYC. Conclusion: LINC01001 promotes the progression of crizotinib-resistant NSCLC by modulating the IGF2BP2/MYC axis. Our research clarifies the specific mechanism of crizotinib-resistance in NSCLC treatment.
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Affiliation(s)
- Meiling Zhang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qian Wang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zihao Ke
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yijing Liu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Huijin Guo
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shencun Fang
- Department of Respiratory Medicine, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China
| | - Kaihua Lu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Zhang H, Shan G, Cai B, Bi G, Chen Z, Liang J, Besskaya V, Zheng Y, Guo W, Wang L, Xu S, Zhan C. Clinicopathological and prognostic implications of ALK rearrangement in patients with completely surgically resected lung adenocarcinoma. Thorac Cancer 2021; 12:3011-3018. [PMID: 34596344 PMCID: PMC8590901 DOI: 10.1111/1759-7714.14170] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 09/11/2021] [Accepted: 09/11/2021] [Indexed: 01/15/2023] Open
Abstract
Background The prognostic significance of ALK rearrangement is still contradictory. Here, we aimed to investigate the clinical characteristics and outcomes of lung adenocarcinoma patients with ALK rearrangement, and analyze whether these patients benefited from targeted therapy. Methods This was a retrospective cohort study of 80 ALK‐rearranged lung adenocarcinoma patients who had undergone radical surgery and another 3031 ALK mutation‐negative patients were retrospectively reviewed for inclusion in this case‐controlled analyses. Overall survival (OS) was evaluated using the Kaplan‐–Meier method. Univariate analysis (UVA) and multivariate analysis (MVA) by the Cox proportional hazards regression identified risk factors that predicted OS. Results Compared to ALK‐negative patients, the ALK rearranged patients were younger, with more non‐smokers, more females, a larger primary tumor was demonstrated, and were a higher pathological stage. In particular, the risk of lymph node metastasis was higher. For patients with surgically‐resected tumors, the prognosis was better for ALK rearranged patients (HR = 0.503; 95% CI: 0.259–0.974, p = 0.041). In addition, for stage II–III patients, targeted therapy was an independent prognostic factor of better OS (HR = 0.159; 95% CI: 0.032–0.801, p = 0.026). Conclusions ALK rearranged lung adenocarcinoma patients who have undergone radical surgery have distinct clinical features. Patients with ALK rearrangement may have a favorable prognosis, and stage II–III patients may benefit from targeted treatment.
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Affiliation(s)
- Huan Zhang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Guangyao Shan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Benjie Cai
- Department of Thoracic Surgery and Urology, Shigatse People's Hospital, Tibet Autonomous Region, China
| | - Guoshu Bi
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhencong Chen
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jiaqi Liang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Valeria Besskaya
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuansheng Zheng
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Weigang Guo
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Thoracic Surgery and Urology, Shigatse People's Hospital, Tibet Autonomous Region, China
| | - Lin Wang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Songtao Xu
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Cheng Zhan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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Li Z, Liu F, Wu S, Ding S, Chen Y, Liu J. Research progress on the drug resistance of ALK kinase inhibitors. Curr Med Chem 2021; 29:2456-2475. [PMID: 34365942 DOI: 10.2174/0929867328666210806120347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 05/09/2021] [Accepted: 05/11/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The fusion and rearrangement of the ALK gene of anaplastic lymphoma kinase is an important cause of a variety of cancers, including non-small cell lung cancer (NSCLC) and anaplastic large cell lymphoma (ALCL). Since crizotinib first came out, many ALK inhibitors have come out one after another, but the fatal flaw in each generation of ALK inhibitors is the body's resistance to drugs. Therefore, how to solve the problem of drug resistance has become an important bottleneck in the application and development of ALK inhibitors. This article briefly introduces the drug resistance of ALK inhibitors and the modified forms of ALK inhibitors, which provide a theoretical basis for solving the drug resistance of ALK inhibitors and the development of a new generation of ALK kinase inhibitors. METHOD We use relevant databases to query relevant literature, and then screen and select based on the relevance and cutting edge of the content. We then summarize and analyze appropriate articles, integrate and classify relevant studies, and finally write articles based on topics. RESULT This article starts with the problem of ALK resistance, first introduces the composition of ALK kinase, and then introduces the problem of resistance of ALK kinase inhibitors. Later, the structural modification to overcome ALK resistance was introduced, and finally, the method to overcome ALK resistance was introduced. CONCLUSION This article summarizes the resistance pathways of ALK kinase inhibitors, and integrates the efforts made to overcome the structural modification of ALK resistance problems, and hopes to provide some inspiration for the development of the next generation of ALK kinase inhibitors.
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Affiliation(s)
- Zhen Li
- College of Pharmacy of Liaoning University, Shenyang, Liaoning 10036. China
| | - Fang Liu
- College of Pharmacy of Liaoning University, Shenyang, Liaoning 10036. China
| | - Shuang Wu
- College of Pharmacy of Liaoning University, Shenyang, Liaoning 10036. China
| | - Shi Ding
- College of Pharmacy of Liaoning University, Shenyang, Liaoning 10036. China
| | - Ye Chen
- College of Pharmacy of Liaoning University, Shenyang, Liaoning 10036. China
| | - Ju Liu
- College of Pharmacy of Liaoning University, Shenyang, Liaoning 10036. China
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Circulating tumor cell copy-number heterogeneity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors. NPJ Precis Oncol 2021; 5:67. [PMID: 34272470 PMCID: PMC8285416 DOI: 10.1038/s41698-021-00203-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 06/08/2021] [Indexed: 11/08/2022] Open
Abstract
Gatekeeper mutations are identified in only 50% of the cases at resistance to Anaplastic Lymphoma Kinase (ALK)-tyrosine kinase inhibitors (TKIs). Circulating tumor cells (CTCs) are relevant tools to identify additional resistance mechanisms and can be sequenced at the single-cell level. Here, we provide in-depth investigation of copy number alteration (CNA) heterogeneity in phenotypically characterized CTCs at resistance to ALK-TKIs in ALK-positive non-small cell lung cancer. Single CTC isolation and phenotyping were performed by DEPArray or fluorescence-activated cell sorting following enrichment and immunofluorescence staining (ALK/cytokeratins/CD45/Hoechst). CNA heterogeneity was evaluated in six ALK-rearranged patients harboring ≥ 10 CTCs/20 mL blood at resistance to 1st and 3rd ALK-TKIs and one presented gatekeeper mutations. Out of 82 CTCs isolated by FACS, 30 (37%) were ALK+/cytokeratins-, 46 (56%) ALK-/cytokeratins+ and 4 (5%) ALK+/cytokeratins+. Sequencing of 43 CTCs showed highly altered CNA profiles and high levels of chromosomal instability (CIN). Half of CTCs displayed a ploidy >2n and 32% experienced whole-genome doubling. Hierarchical clustering showed significant intra-patient and wide inter-patient CTC diversity. Classification of 121 oncogenic drivers revealed the predominant activation of cell cycle and DNA repair pathways and of RTK/RAS and PI3K to a lower frequency. CTCs showed wide CNA heterogeneity and elevated CIN at resistance to ALK-TKIs. The emergence of epithelial ALK-negative CTCs may drive resistance through activation of bypass signaling pathways, while ALK-rearranged CTCs showed epithelial-to-mesenchymal transition characteristics potentially contributing to ALK-TKI resistance. Comprehensive analysis of CTCs could be of great help to clinicians for precision medicine and resistance to ALK-targeted therapies.
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Haratake N, Toyokawa G, Seto T, Tagawa T, Okamoto T, Yamazaki K, Takeo S, Mori M. The mechanisms of resistance to second- and third-generation ALK inhibitors and strategies to overcome such resistance. Expert Rev Anticancer Ther 2021; 21:975-988. [PMID: 34110954 DOI: 10.1080/14737140.2021.1940964] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
INTRODUCTION Anaplastic lymphoma kinase (ALK) inhibitors are widely known to contribute to the long-term survival of ALK-rearranged non-small cell lung cancer (NSCLC) patients. Based on clinical trial data, treatment with second- or third-generation ALK inhibitors can be initiated after crizotinib therapy without analyzing resistance mechanisms, and some randomized trials have recently shown the superiority of second- or third-generation ALK inhibitors over crizotinib as the initial treatment; however, the optimal treatment for patients who relapse while on second- or third-generation ALK inhibitors is not well-defined. AREAS COVERED This review provides an overview of the mechanisms of resistance to second- or third-generation ALK inhibitors that have been identified in both clinical and pre-clinical settings, and introduces strategies for overcoming resistance and discusses ongoing clinical trials. EXPERT OPINION The comprehensive elucidation of both ALK-dependent and ALK-independent resistance mechanisms is necessary to improve the prognosis of patients with ALK-rearranged NSCLC. Liquid biopsy to clarify these mechanisms of resistance might play an important role in the near future.
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Affiliation(s)
- Naoki Haratake
- Department of Thoracic Oncology, National Hospital Organization, Kyushu Cancer Center, Fukuoka, Japan.,Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Gouji Toyokawa
- Department of Thoracic Surgery, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, Fukuoka, Japan
| | - Takashi Seto
- Department of Thoracic Oncology, National Hospital Organization, Kyushu Cancer Center, Fukuoka, Japan
| | - Tetsuzo Tagawa
- Department of Thoracic Oncology, National Hospital Organization, Kyushu Cancer Center, Fukuoka, Japan
| | - Tasuro Okamoto
- Department of Thoracic Oncology, National Hospital Organization, Kyushu Cancer Center, Fukuoka, Japan
| | - Koji Yamazaki
- Department of Thoracic Surgery, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, Fukuoka, Japan
| | - Sadanori Takeo
- Department of Thoracic Surgery, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, Fukuoka, Japan
| | - Masaki Mori
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Antoni D, Burckel H, Noel G. Combining Radiation Therapy with ALK Inhibitors in Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer (NSCLC): A Clinical and Preclinical Overview. Cancers (Basel) 2021; 13:2394. [PMID: 34063424 PMCID: PMC8156706 DOI: 10.3390/cancers13102394] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/12/2021] [Accepted: 05/13/2021] [Indexed: 12/25/2022] Open
Abstract
Over the past years, the identification of genetic alterations in oncogenic drivers in non-small cell lung cancer (NSCLC) has significantly and favorably transformed the outcome of patients who can benefit from targeted therapies such as tyrosine kinase inhibitors. Among these genetic alterations, anaplastic lymphoma kinase (ALK) rearrangements were discovered in 2007 and are present in 3-5% of patients with NSCLC. In addition, radiotherapy remains one of the cornerstones of NSCLC treatment. Moreover, improvements in the field of radiotherapy with the use of hypofractionated or ablative stereotactic radiotherapy have led to a better outcome for localized or oligometastatic NSCLC. To date, the effects of the combination of ALK inhibitors and radiotherapy are unclear in terms of safety and efficacy but could potently improve treatment. In this manuscript, we provide a clinical and preclinical overview of combining radiation therapy with ALK inhibitors in anaplastic lymphoma kinase-positive non-small cell lung cancer.
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Affiliation(s)
- Delphine Antoni
- Paul Strauss Comprehensive Cancer Center, Radiobiology Laboratory, Institut de Cancérologie Strasbourg Europe (ICANS), Strasbourg University, UNICANCER, 67000 Strasbourg, France; (H.B.); (G.N.)
- Department of Radiotherapy, ICANS, Institut de Cancérologie Strasbourg Europe, 17 rue Albert Calmette, CEDEX, 67200 Strasbourg, France
| | - Hélène Burckel
- Paul Strauss Comprehensive Cancer Center, Radiobiology Laboratory, Institut de Cancérologie Strasbourg Europe (ICANS), Strasbourg University, UNICANCER, 67000 Strasbourg, France; (H.B.); (G.N.)
| | - Georges Noel
- Paul Strauss Comprehensive Cancer Center, Radiobiology Laboratory, Institut de Cancérologie Strasbourg Europe (ICANS), Strasbourg University, UNICANCER, 67000 Strasbourg, France; (H.B.); (G.N.)
- Department of Radiotherapy, ICANS, Institut de Cancérologie Strasbourg Europe, 17 rue Albert Calmette, CEDEX, 67200 Strasbourg, France
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45
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Haga Y, Marrocco I, Noronha A, Uribe ML, Nataraj NB, Sekar A, Drago-Garcia D, Borgoni S, Lindzen M, Giri S, Wiemann S, Tsutsumi Y, Yarden Y. Host-Dependent Phenotypic Resistance to EGFR Tyrosine Kinase Inhibitors. Cancer Res 2021; 81:3862-3875. [PMID: 33941614 DOI: 10.1158/0008-5472.can-20-3555] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 03/01/2021] [Accepted: 04/28/2021] [Indexed: 11/16/2022]
Abstract
Lung cancers driven by mutant forms of EGFR invariably develop resistance to kinase inhibitors, often due to secondary mutations. Here we describe an unconventional mechanism of resistance to dacomitinib, a newly approved covalent EGFR kinase inhibitor, and uncover a previously unknown step of resistance acquisition. Dacomitinib-resistant (DR) derivatives of lung cancer cells were established by means of gradually increasing dacomitinib concentrations. These DR cells acquired no secondary mutations in the kinase or other domains of EGFR. Along with resistance to other EGFR inhibitors, DR cells acquired features characteristic to epithelial-mesenchymal transition, including an expanded population of aldehyde dehydrogenase-positive cells and upregulation of AXL, a receptor previously implicated in drug resistance. Unexpectedly, when implanted in animals, DR cells reverted to a dacomitinib-sensitive state. Nevertheless, cell lines derived from regressing tumors displayed renewed resistance when cultured in vitro. Three-dimensional and cocultures along with additional analyses indicated lack of involvement of hypoxia, fibroblasts, and immune cells in phenotype reversal, implying that other host-dependent mechanisms might nullify nonmutational modes of resistance. Thus, similar to the phenotypic resistance of bacteria treated with antibiotics, the reversible resisters described here likely evolve from drug-tolerant persisters and give rise to the irreversible, secondary mutation-driven nonreversible resister state. SIGNIFICANCE: This study reports that stepwise acquisition of kinase inhibitor resistance in lung cancers driven by mutant EGFR comprises a nonmutational, reversible resister state. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/14/3862/F1.large.jpg.
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Affiliation(s)
- Yuya Haga
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.,Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Ilaria Marrocco
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Ashish Noronha
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Mary Luz Uribe
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | | | - Arunachalam Sekar
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Diana Drago-Garcia
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Simone Borgoni
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Moshit Lindzen
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Suvendu Giri
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Stefan Wiemann
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Yasuo Tsutsumi
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.,Global Center for Medical Engineering and Informatics, Osaka University, Osaka, Japan
| | - Yosef Yarden
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
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IL10RA modulates crizotinib sensitivity in NPM1-ALK+ anaplastic large cell lymphoma. Blood 2021; 136:1657-1669. [PMID: 32573700 DOI: 10.1182/blood.2019003793] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Accepted: 05/19/2020] [Indexed: 02/08/2023] Open
Abstract
Anaplastic large cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive anaplastic lymphoma kinase (ALK) fusion protein. ALK inhibitors, such as crizotinib, provide alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by nucleophosmin 1 (NPM1)-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54% to 90% in clinical trials; however, a subset of patients progressed within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) activation and knockout screens in ALCL cell lines, combined with RNA sequencing data derived from ALK inhibitor-relapsed patient tumors, we show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of interleukin 10 receptor subunit alpha (IL10RA). Elevated IL10RA expression rewires the STAT3 signaling pathway, bypassing otherwise critical phosphorylation by NPM1-ALK. IL-10RA expression does not correlate with response to standard chemotherapy in pediatric patients, suggesting that a combination of crizotinib and chemotherapy could prevent ALK inhibitor resistance-specific relapse.
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Gupta N, Hanley MJ, Kerstein D, Tugnait M, Narasimhan N, Marbury TC, Venkatakrishnan K. Effect of severe renal impairment on the pharmacokinetics of brigatinib. Invest New Drugs 2021; 39:1306-1314. [PMID: 33742299 PMCID: PMC8426299 DOI: 10.1007/s10637-021-01095-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 03/04/2021] [Indexed: 01/27/2023]
Abstract
Background Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, targets activated, mutant forms of ALK and overcomes mechanisms of resistance to the ALK inhibitors crizotinib, ceritinib, and alectinib. Brigatinib is approved in multiple countries for treatment of patients with ALK-positive non–small cell lung cancer. Based on population pharmacokinetic (PK) analyses, no dosage adjustment is required for patients with mild or moderate renal impairment. Methods An open-label, single-dose study was conducted to evaluate the PK of brigatinib (90 mg) in patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2; n = 8) and matched healthy volunteers with normal renal function (estimated glomerular filtration rate ≥ 90 mL/min/1.73 m2; n = 8). Plasma and urine were collected for the determination of plasma protein binding and estimation of plasma and urine PK parameters. Results Plasma protein binding of brigatinib was similar between patients with severe renal impairment (92 % bound) and matched healthy volunteers with normal renal function (91 % bound). Unbound brigatinib exposure (area under the plasma concentration-time curve from time zero to infinity) was approximately 92 % higher in patients with severe renal impairment compared with healthy volunteers with normal renal function. The renal clearance of brigatinib in patients with severe renal impairment was approximately 20 % of that observed in volunteers with normal renal function. Conclusions These findings support a brigatinib dosage reduction of approximately 50 % in patients with severe renal impairment. Trial registry: Not applicable.
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Affiliation(s)
- Neeraj Gupta
- Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 40 Landsdowne Street, Cambridge, MA, 02139, USA.
| | - Michael J Hanley
- Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 40 Landsdowne Street, Cambridge, MA, 02139, USA
| | - David Kerstein
- Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 40 Landsdowne Street, Cambridge, MA, 02139, USA.,Anchiano Therapeutics, Cambridge, MA, USA
| | - Meera Tugnait
- Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 40 Landsdowne Street, Cambridge, MA, 02139, USA.,Spectrum Pharmaceuticals, Inc., Cambridge, MA, USA
| | - Narayana Narasimhan
- Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 40 Landsdowne Street, Cambridge, MA, 02139, USA.,Verastem Oncology, Needham, MA, USA
| | | | - Karthik Venkatakrishnan
- Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 40 Landsdowne Street, Cambridge, MA, 02139, USA.,EMD Serono, Inc., Billerica, MA, USA
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Harada D, Isozaki H, Kozuki T, Yokoyama T, Yoshioka H, Bessho A, Hosokawa S, Takata I, Takigawa N, Hotta K, Kiura K. Crizotinib for recurring non-small-cell lung cancer with EML4-ALK fusion genes previously treated with alectinib: A phase II trial. Thorac Cancer 2021; 12:643-649. [PMID: 33470536 PMCID: PMC7919114 DOI: 10.1111/1759-7714.13825] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 12/22/2020] [Accepted: 12/22/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The efficacy of crizotinib treatment for recurring EML4-ALK-positive non-small cell lung cancer (NSCLC) previously treated with alectinib is unclear. Based on our preclinical findings regarding hepatocyte growth factor/mesenchymal epithelial transition (MET) pathway activation as a potential mechanism of acquired resistance to alectinib, we conducted a phase II trial of the anaplastic lymphoma kinase/MET inhibitor, crizotinib, in patients with alectinib-refractory, EML4-ALK-positive NSCLC. METHODS Patients with ALK-rearranged tumors treated with alectinib immediately before enrolling in the trial received crizotinib monotherapy. The objective response rate was the primary outcome of interest. RESULTS Nine (100%) patients achieved a partial response with alectinib therapy with a median treatment duration of 6.7 months. Crizotinib was administered with a median treatment interval of 50 (range, 20-433) days. The overall response rate was 33.3% (90% confidence interval [CI]: 9.8-65.5 and 95% CI: 7.5-70.1), which did not reach the predefined criteria of 50%. Two (22%) patients who achieved a partial response had brain metastases at baseline. Progression-free survival (median, 2.2 months) was not affected by the duration of treatment with alectinib. The median survival time was 24.1 months. The most common adverse events were an increased aspartate transaminase/alanine transaminase (AST/ALT) ratio (44%) and appetite loss (33%); one patient developed transient grade 4 AST/ALT elevation, resulting in treatment discontinuation. Other adverse events were consistent with those previously reported; no treatment-related deaths occurred. CONCLUSIONS Although the desired response rate was not achieved, crizotinib monotherapy following treatment with alectinib showed efficacy alongside previously described adverse events.
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Affiliation(s)
- Daijiro Harada
- Department of Thoracic OncologyNational Hospital Organization Shikoku Cancer CenterMatsuyamaJapan
| | - Hideko Isozaki
- Department of Clinical PharmaceuticsOkayama University HospitalOkayamaJapan
- Department of Respiratory MedicineOkayama University HospitalOkayamaJapan
| | - Toshiyuki Kozuki
- Department of Thoracic OncologyNational Hospital Organization Shikoku Cancer CenterMatsuyamaJapan
| | - Toshihide Yokoyama
- Department of Respiratory MedicineKurashiki Central HospitalKurashikiJapan
| | - Hiroshige Yoshioka
- Department of Respiratory MedicineKurashiki Central HospitalKurashikiJapan
- Department of Thoracic OncologyKansai Medical University HospitalHirakataJapan
| | - Akihiro Bessho
- Department of Respiratory MedicineJapanese Red Cross Okayama HospitalOkayamaJapan
| | - Shinobu Hosokawa
- Department of Respiratory MedicineJapanese Red Cross Okayama HospitalOkayamaJapan
| | - Ichiro Takata
- Department of Internal MedicineFukuyama City HospitalFukuyamaJapan
| | - Nagio Takigawa
- Department of General Internal Medicine 4Kawasaki Medical SchoolOkayamaJapan
| | - Katsuyuki Hotta
- Department of Respiratory MedicineOkayama University HospitalOkayamaJapan
- Center for Clinical Innovative MedicineOkayama University HospitalOkayamaJapan
| | - Katsuyuki Kiura
- Department of Respiratory MedicineOkayama University HospitalOkayamaJapan
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Yoshimura C, Nagatoishi S, Kuroda D, Kodama Y, Uno T, Kitade M, Chong-Takata K, Oshiumi H, Muraoka H, Yamashita S, Kawai Y, Ohkubo S, Tsumoto K. Thermodynamic Dissection of Potency and Selectivity of Cytosolic Hsp90 Inhibitors. J Med Chem 2021; 64:2669-2677. [PMID: 33621080 DOI: 10.1021/acs.jmedchem.0c01715] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The cytosolic Hsp90-selective inhibitor TAS-116 has an acceptable safety profile and promising antitumor activity in clinical trials. We examined the binding characteristics of TAS-116 and its analogs to determine the impact of the ligand binding mode on selectivity for cytosolic Hsp90. Analyses of the co-crystal structure of Hsp90 and inhibitor TAS-116 suggest that TAS-116 interacts with the ATP-binding pocket, the ATP lid region, and the hydrophobic pocket. A competitive isothermal titration calorimetry analysis confirmed that a small fragment of TAS-116 (THS-510) docks into the lid region and hydrophobic pockets without binding to the ATP-binding pocket. THS-510 exhibited enthalpy-driven binding to Hsp90α and selectively inhibited cytosolic Hsp90 activity. The heat capacity change of THS-510 binding was positive, likely due to the induced conformational rearrangement of Hsp90. Thus, we concluded that interactions with the hydrophobic pocket of Hsp90 determine potency and selectivity of TAS-116 and derivatives for the cytosolic Hsp90 isoform.
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Affiliation(s)
- Chihoko Yoshimura
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki 300-2611, Japan
| | - Satoru Nagatoishi
- The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
| | - Daisuke Kuroda
- Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Yasuo Kodama
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki 300-2611, Japan
| | - Takao Uno
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki 300-2611, Japan
| | - Makoto Kitade
- Chemical Technology Laboratory, CMC Division, Taiho Pharmaceutical Co. Ltd., Kamikawamachi, Kodama-gun, Saitama 367-0241, Japan
| | - Khoontee Chong-Takata
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki 300-2611, Japan
| | - Hiromi Oshiumi
- Formulation Research, CMC Division, Taiho Pharmaceutical Co. Ltd., Kawauchi-cho, Tokushima 771-0194, Japan
| | - Hiromi Muraoka
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki 300-2611, Japan
| | - Satoshi Yamashita
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki 300-2611, Japan
| | - Yuichi Kawai
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki 300-2611, Japan
| | - Shuichi Ohkubo
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki 300-2611, Japan
| | - Kouhei Tsumoto
- The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.,Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
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50
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Tabbò F, Reale ML, Bironzo P, Scagliotti GV. Resistance to anaplastic lymphoma kinase inhibitors: knowing the enemy is half the battle won. Transl Lung Cancer Res 2021; 9:2545-2556. [PMID: 33489817 PMCID: PMC7815358 DOI: 10.21037/tlcr-20-372] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Anaplastic lymphoma kinase (ALK) translocations are responsible of neoplastic transformation in a limited subset of non-small cell lung cancer (NSCLC) patients. In recent years outcomes of these patients improved due to the development and clinical availability of specific and extremely active targeted therapies [i.e., next-generation Tyrosine Kinase Inhibitors (TKI)]: ALK+ patients are now reaching impressive results when treated with more potent inhibitors upfront with an average median progression-free survival (mPFS) around 35 months. However, under drug pressure, cancer cells develop resistance and patients eventually progress. Multiple mechanisms of intrinsic or acquired resistance have been extensively characterized. Less potent ALK inhibitors (ALKi)—like crizotinib—usually tend to induce a large spectrum of secondary intra-kinase mutations; however, these alterations may be observed also after sequential administration of multiple ALKi. Noteworthy, neoplastic cells may evade ALK targeting through a myriad of different mechanisms involving cell-stroma interaction, activation of parallel signaling pathways, intracellular downstream adaptation and histological reshaping, as relevant molecular events. Often these phenomena are restricted to a limited number of cases or even can be patient-specific, thus hindering the development of therapeutic strategies largely applicable. Consequently, the recognition of specific resistance mechanisms seldom translates in clinical opportunities. Management of ALK+ patients is drastically changed and deciphering the molecular biology underlying this disease during treatment is of paramount relevance. The bedrock of resistance to TKI is that, after the diagnosis, we face with a different disease that needs to be re-characterized through tissue or/and liquid biopsies. Understanding molecular pathways driving the resistant phenotype will give us the chance to know what we are dealing with and, rather than choose an empirical approach, will help us to properly define the best targeted treatment for these patients.
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Affiliation(s)
- Fabrizio Tabbò
- Department of Oncology, University of Turin, San Luigi Hospital, Orbassano, TO, Italy
| | - Maria Lucia Reale
- Department of Oncology, University of Turin, San Luigi Hospital, Orbassano, TO, Italy
| | - Paolo Bironzo
- Department of Oncology, University of Turin, San Luigi Hospital, Orbassano, TO, Italy
| | - Giorgio V Scagliotti
- Department of Oncology, University of Turin, San Luigi Hospital, Orbassano, TO, Italy
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