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Sun X, Ren Q, Liu X, Tan H, Zhan Z, Lin E, Long Y, Hong X, Zhou L, Liu Y. Matrix metalloproteinase-10 promotes kidney fibrosis by transactivating β-catenin signaling. Cell Death Discov 2025; 11:241. [PMID: 40382334 DOI: 10.1038/s41420-025-02521-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 04/25/2025] [Accepted: 05/01/2025] [Indexed: 05/20/2025] Open
Abstract
Kidney fibrosis is characterized by excessive accumulation of extracellular matrix (ECM) and serves as a hallmark of chronic kidney disease (CKD). The turnover of ECM is controlled by a family of matrix metalloproteinases (MMPs), endopeptidases that play a crucial role in ECM remodeling and other cellular processes. In this study, we demonstrate that MMP-10 was upregulated in a variety of animal models of kidney fibrosis and human kidney biopsies from CKD patients. Bioinformatics analyses and experimental validation reveal that MMP-10 activated β-catenin in a Wnt-independent fashion. Knockdown of endogenous MMP-10 expression in vivo inhibited β-catenin activation and ameliorated kidney injury and fibrotic lesions, whereas over-expression of exogenous MMP-10 aggravated β-catenin activation and kidney fibrosis after injury. We found that MMP-10 cleaved and activated heparin-binding EGF-like growth factor (HB-EGF) via ectodomain shedding, leading to EGF receptor (EGFR) tyrosine phosphorylation and β-catenin transactivation via a cascade of events involving extracellular signal-regulated kinases and glycogen synthase kinase-3β. Consistently, treatment with erlotinib, a small-molecule EGFR inhibitor, effectively mitigated MMP-10-mediated kidney injury and fibrotic lesions in a dose-dependent fashion. Furthermore, β-catenin activation reciprocally upregulated the expression of MMP-10, thereby perpetuating kidney damage by forming a vicious cycle. Collectively, these results underscore that MMP-10 promotes kidney fibrosis through EGFR-mediated transactivating β-catenin in a Wnt-independent fashion. Our findings suggest that targeting MMP-10 could be a novel strategy for treatment of fibrotic CKD.
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Affiliation(s)
- Xiaoli Sun
- State Key Laboratory of Multi-organ Injury Prevention and Treatment, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, China
| | - Qian Ren
- State Key Laboratory of Multi-organ Injury Prevention and Treatment, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, China
| | - Xi Liu
- State Key Laboratory of Multi-organ Injury Prevention and Treatment, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, China
| | - Huishi Tan
- State Key Laboratory of Multi-organ Injury Prevention and Treatment, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, China
| | - Zhanji Zhan
- State Key Laboratory of Multi-organ Injury Prevention and Treatment, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, China
| | - Enqing Lin
- State Key Laboratory of Multi-organ Injury Prevention and Treatment, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, China
| | - Yinyi Long
- State Key Laboratory of Multi-organ Injury Prevention and Treatment, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, China
| | - Xue Hong
- State Key Laboratory of Multi-organ Injury Prevention and Treatment, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, China
| | - Lili Zhou
- State Key Laboratory of Multi-organ Injury Prevention and Treatment, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
- Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, China.
| | - Youhua Liu
- State Key Laboratory of Multi-organ Injury Prevention and Treatment, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
- Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, China.
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2
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Constantinidou A, Jones RL. Maintenance treatment in sarcomas: who is it for? Ann Oncol 2025:S0923-7534(25)00194-2. [PMID: 40374112 DOI: 10.1016/j.annonc.2025.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2025] [Accepted: 05/06/2025] [Indexed: 05/17/2025] Open
Affiliation(s)
- A Constantinidou
- Medical School University of Cyprus, Nicosia, Cyprus; BoC Oncology Centre, Nicosia, Cyprus
| | - R L Jones
- Sarcoma Unit, The Royal Marsden Hospital, London, United Kingdom; Institute of Cancer Research, London, United Kingdom.
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3
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Wei JR, Lu MY, Wei TH, Fleishman JS, Yu H, Chen XL, Kong XT, Sun SL, Li NG, Yang Y, Ni HW. Overcoming cancer therapy resistance: From drug innovation to therapeutics. Drug Resist Updat 2025; 81:101229. [PMID: 40081221 DOI: 10.1016/j.drup.2025.101229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 02/18/2025] [Accepted: 03/03/2025] [Indexed: 03/15/2025]
Abstract
One of the major limitations of cancer therapy is the emergence of drug resistance. This review amis to provide a focused analysis of the multifactorial mechanisms underlying therapy resistance,with an emphasis on actionable insights for developing novel therapeutic strategies. It concisely outlines key factors contributing to therapy resistance, including drug delivery barriers, cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT), cancer heterogeneity, tumor microenvironment (TME), genetic mutations, and alterlations in gene expression. Additionally, we explore how tumors evade targeted therapies through pathway-specific mechanisms that restore disrupted signaling pathways. The review critically evaluates innovative strategies designed to sensitize resistant tumor cells, such as targeted protein dedgradation, antibody-drug conjugates, structure-based drug design, allosteric drugs, multitarget drugs, nanomedicine and others We also highlight the importance of understanding the pharmacological actions of these agents and their integration into treatment regimens. By synthesizing current knowledge and identifying gaps in our understanding, this review aims to guide future research and improve patient outcomes in cancer therapy.
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Affiliation(s)
- Jin-Rui Wei
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210029, China; The First Clinical College of Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Meng-Yi Lu
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 210029, China
| | - Tian-Hua Wei
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Joshua S Fleishman
- College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Hui Yu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210029, China
| | - Xiao-Li Chen
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210029, China
| | - Xiang-Tu Kong
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210029, China
| | - Shan-Liang Sun
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China.
| | - Nian-Guang Li
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Ye Yang
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China; School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Hai-Wen Ni
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210029, China.
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Fu MJ, Jin H, Wang SP, Shen L, Liu HM, Liu Y, Zheng YC, Dai XJ. Unleashing the Power of Covalent Drugs for Protein Degradation. Med Res Rev 2025. [PMID: 39834319 DOI: 10.1002/med.22101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 11/28/2024] [Accepted: 01/06/2025] [Indexed: 01/22/2025]
Abstract
Targeted protein degradation (TPD) has emerged as a significant therapeutic approach for a variety of diseases, including cancer. Advances in TPD techniques, such as molecular glue (MG) and lysosome-dependent strategies, have shown substantial progress since the inception of the first PROTAC in 2001. The PROTAC methodology represents the forefront of TPD technology, with ongoing evaluation in more than 20 clinical trials for the treatment of diverse medical conditions. Two prominent PROTACs, ARV-471 and ARV-110, are currently undergoing phase III and II clinical trials, respectively. Traditional PROTACs are encountering obstacles such as limited binding affinity and a restricted range of E3 ligase ligands for facilitating the protein of interest (POI) degradation. Covalent medicines offer the potential to enhance PROTAC efficacy by enabling the targeting of previously considered "undruggable" shallow binding sites. Strategic alterations allow PROTAC to establish covalent connections with particular target proteins, including Kirsten rat sarcoma viral oncogene homolog (KRAS), Bruton's tyrosine kinase (BTK), epidermal growth factor receptor (EGFR), as well as E3 ligases such as DDB1 and CUL4 associated factor 16 (DCAF16) and Kelch-like ECH-associated protein 1 (Keap1). The concept of covalent degradation has also been utilized in various new forms of degraders, including covalent molecule glue (MG), in-cell click-formed proteolysis targeting chimera (CLIPTAC), HaloPROTAC, lysosome-targeting chimera (LYTAC) and GlueTAC. This review focuses on recent advancements in covalent degraders beyond covalent PROTACs and examines obstacles and future directions pertinent to this field.
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Affiliation(s)
- Meng-Jie Fu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Hang Jin
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Shao-Peng Wang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Liang Shen
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Hong-Min Liu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Ying Liu
- Henan Engineering Research Center for Application & Translation of Precision Clinical Pharmacy, Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yi-Chao Zheng
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Xing-Jie Dai
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- Key Laboratory of Cardio-Cerebrovascular Drug, China Meheco Topfond Pharmaceutical Company, Zhumadian, Henan, China
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5
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Gelsomino F, Boni L, Tiseo M, Ricciardi S, Rocco D, Cortinovis DL, Proietto M, Cogoni A, Pasello G, Camerini A, Sperandi F, Colantonio I, Metro G, Mazzoni F, Baldini E, Veccia A, Bennicelli E, Cecilia Bettini A, Tognetto M, Ardizzoni A. An open-label, randomized phase III study of early switch maintenance vs delayed second-line nivolumab in advanced stage squamous non-small cell lung cancer (NSCLC) patients after standard first-line platinum-based chemotherapy-EDEN trial GOIRC 04-2016. Lung Cancer 2025; 199:108059. [PMID: 39700681 DOI: 10.1016/j.lungcan.2024.108059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 11/06/2024] [Accepted: 12/11/2024] [Indexed: 12/21/2024]
Abstract
BACKGROUND As for squamous (Sq)-NSCLC, Checkmate-017 trial showed a significant overall survival (OS) improvement in favor of Nivolumab (Nivo) over Docetaxel in 2nd-line. We hypothesized that anticipating Nivo use, as early switch maintenance after 1st-line chemotherapy (CHT), might have improved survival as compared to delayed 2nd-line treatment. METHODS EDEN was an open-label, 2-arm, phase III study which randomized (1:1) stage IIIB/IV Sq-NSCLC pts non-progressive after 1st-line platinum-based CHT, to receive early Nivo as switch maintenance (Arm A) or standard best supportive care followed by 2nd-line Nivo at disease progression (Arm B). In both arms, Nivo was administered at the dose of 240 mg i.v. every 2 weeks until progressive disease, intolerable toxicity, or for a maximum of 2 years. The primary endpoint was OS. RESULTS From Sep 2017 to Aug 2020 125 patients (62 Arm A vs 63 Arm B) were randomized from 32 Italian centers. Accrual was stopped early, before the planned sample size (388 pts) was reached, because of registration of ICPIs in 1st-line. Most patients were male (79.2 %), current/former smokers (93.6 %), had stage IV (74.4 %), performance status 0-1 (98.4 %). mOS (95 % CI) was 14.9 (10.4-18.6) months in arm A vs 18.8 (14.4-21.1) months in arm B (HR 1.09, 95 %CI 0.74-1.62, p = 0.659). CONCLUSIONS In advanced Sq-NSCLC, the use of Nivo as switch maintenance after 1st-line CHT, does not improve OS compared to its use as 2nd-line. Although the optimal use of ICPIs remains in 1st-line, its role as maintenance has to be better investigated. CLINICALTRIALS gov: registration number: NCT03542461.
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Affiliation(s)
- Francesco Gelsomino
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
| | - Luca Boni
- SC Epidemiologia Clinica IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Marcello Tiseo
- Department of Medicine and Surgery, University of Parma, Parma, Italy 2Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | | | - Danilo Rocco
- Department of Pulmonary Oncology, AORN dei Colli Monaldi, Napoli, Italy
| | - Diego L Cortinovis
- Fondazione IRCCS San Gerardo dei Tintori, Università degli Studi di Milano-Bicocca, Monza, Italy
| | - Manuela Proietto
- Department of Oncology and Hematology, AUSL Piacenza, Piacenza, Italy
| | | | - Giulia Pasello
- Oncology 2, Istituto Oncologico Veneto IOV IRCCS, Padova, Italy, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Andrea Camerini
- Medical Oncology, Versilia Hospital - Azienda USL Toscana nord ovest, Lido di Camaiore, Italy
| | - Francesca Sperandi
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | | | - Giulio Metro
- Medical Oncology, Santa Maria Della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy
| | | | | | | | - Elisa Bennicelli
- IRCCS Ospedale Policlinico San Martino, U.O.C. Oncologia Medica 2, Genoa, Italy
| | | | | | - Andrea Ardizzoni
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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6
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Zhong G, Chang X, Xie W, Zhou X. Targeted protein degradation: advances in drug discovery and clinical practice. Signal Transduct Target Ther 2024; 9:308. [PMID: 39500878 PMCID: PMC11539257 DOI: 10.1038/s41392-024-02004-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 08/19/2024] [Accepted: 09/28/2024] [Indexed: 11/08/2024] Open
Abstract
Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing a stark contrast to traditional therapeutic approaches like small molecule inhibitors that primarily focus on inhibiting protein function. This advanced technology capitalizes on the cell's intrinsic proteolytic systems, including the proteasome and lysosomal pathways, to selectively eliminate disease-causing proteins. TPD not only enhances the efficacy of treatments but also expands the scope of protein degradation applications. Despite its considerable potential, TPD faces challenges related to the properties of the drugs and their rational design. This review thoroughly explores the mechanisms and clinical advancements of TPD, from its initial conceptualization to practical implementation, with a particular focus on proteolysis-targeting chimeras and molecular glues. In addition, the review delves into emerging technologies and methodologies aimed at addressing these challenges and enhancing therapeutic efficacy. We also discuss the significant clinical trials and highlight the promising therapeutic outcomes associated with TPD drugs, illustrating their potential to transform the treatment landscape. Furthermore, the review considers the benefits of combining TPD with other therapies to enhance overall treatment effectiveness and overcome drug resistance. The future directions of TPD applications are also explored, presenting an optimistic perspective on further innovations. By offering a comprehensive overview of the current innovations and the challenges faced, this review assesses the transformative potential of TPD in revolutionizing drug development and disease management, setting the stage for a new era in medical therapy.
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Affiliation(s)
- Guangcai Zhong
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China
| | - Xiaoyu Chang
- School of Pharmaceutical Sciences, Pingyuan Laboratory, Zhengzhou University, Zhengzhou, 450001, China
| | - Weilin Xie
- Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
| | - Xiangxiang Zhou
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China.
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7
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Chartier L, Belot A, Chaillol I, Elsensohn MH, Portugues C, Fournier M, Joubert C, Gat E, Pizot C, Fogarty P, Murairi T, Ammar RO, Paget J, Cherblanc F, Ricci R, Vercellino L, Kanoun S, Cottereau AS, Thieblemont C, Casasnovas O. Precautions to Consider in the Analysis of Prognostic and Predictive Indices. J Nucl Med 2024; 65:1672-1678. [PMID: 39486863 DOI: 10.2967/jnumed.123.267021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 09/10/2024] [Indexed: 11/04/2024] Open
Abstract
Understanding the differences between prognostic and predictive indices is imperative for medical research advances. We have developed a new prognostic measure that will identify the strengths, limitations, and potential applications in clinical practice.
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Affiliation(s)
- Loïc Chartier
- Biostatistics Department, LYSARC, Hôpital Lyon Sud, Pierre-Bénite, France;
| | - Aurélien Belot
- Biostatistics Department, LYSARC, Hôpital Lyon Sud, Pierre-Bénite, France
| | - Isabelle Chaillol
- Biostatistics Department, LYSARC, Hôpital Lyon Sud, Pierre-Bénite, France
| | | | - Cédric Portugues
- Biostatistics Department, LYSARC, Hôpital Lyon Sud, Pierre-Bénite, France
| | | | - Clémentine Joubert
- Biostatistics Department, LYSARC, Hôpital Lyon Sud, Pierre-Bénite, France
| | - Elodie Gat
- Biostatistics Department, LYSARC, Hôpital Lyon Sud, Pierre-Bénite, France
| | - Cécile Pizot
- Biostatistics Department, LYSARC, Hôpital Lyon Sud, Pierre-Bénite, France
| | - Patrick Fogarty
- Biostatistics Department, LYSARC, Hôpital Lyon Sud, Pierre-Bénite, France
| | - Tesla Murairi
- Biostatistics Department, LYSARC, Hôpital Lyon Sud, Pierre-Bénite, France
| | - Romain Ould Ammar
- Biostatistics Department, LYSARC, Hôpital Lyon Sud, Pierre-Bénite, France
| | - Jérôme Paget
- Biostatistics Department, LYSARC, Hôpital Lyon Sud, Pierre-Bénite, France
| | - Fanny Cherblanc
- Medical Department, LYSARC, Hôpital Lyon Sud, Pierre-Bénite, France
| | - Romain Ricci
- Imaging Department, LYSARC, Hôpital Henri-Mondor, Créteil, France
| | - Laetitia Vercellino
- Department of Nuclear Medicine, Hôpital Saint-Louis, AP-HP, INSERM UMR S942, Université Paris Cité, Paris, France
| | - Salim Kanoun
- Department of Hematology, Cancer Research Center of Toulouse, Team 9, INSERM Unité Mixte de Recherche 1037, Toulouse, France
| | | | - Catherine Thieblemont
- Assistance Publique-Hôpitaux de Paris, Université de Paris, and Hemato-Oncologie, Hôpital Saint-Louis, Paris, France; and
| | - Olivier Casasnovas
- Department of Hematology and INSERM 1231, CHU Dijon Bourgogne, Dijon, France
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8
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Wang T, Wang Y, Lu J, Chen J, Wang L, Ouyang Z, Ouyang W, Hu C, Weng J, Zhang JQ. Design, synthesis and bioevaluation of dual EGFR-PI3Kα inhibitors for potential treatment of NSCLC. Bioorg Chem 2024; 151:107714. [PMID: 39167867 DOI: 10.1016/j.bioorg.2024.107714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 07/23/2024] [Accepted: 08/09/2024] [Indexed: 08/23/2024]
Abstract
Aberrant activation or mutation of the EGFR-PI3K-Akt-mTOR signaling pathway has been implicated in a wide range of human cancers, especially non-small-cell lung cancer (NSCLC). Thus, dual inhibition of EGFR and PI3K has been investigated as a promising strategy to address acquired drug resistance resulting from the use of tyrosine kinase inhibitors. A series of dual EGFR/PI3Kα inhibitors was synthesized using pharmacophore hybridization of the third-generation EGFR inhibitor olmutinib and the PI3Kα selective inhibitor TAK-117. The optimal compound 30k showed potent kinase inhibitory activities with IC50 values of 3.6 and 30.0 nM against EGFRL858R/T790M and PI3Kα, respectively. Compound 30k exhibited a significant antiproliferative effect in NCI-H1975 cells with a higher selectivity profile than olmutinib. The potential antitumor mechanism, molecular binding modes, and in vitro metabolic stability of compound 30k were also clarified.
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Affiliation(s)
- Tingliang Wang
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang 561113, China; Department of Pharmacy, Liupanshui Municipal People's Hospital, Liupanshui 553000, China
| | - Yujie Wang
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang 561113, China
| | - Jiangrong Lu
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang 561113, China
| | - Junxiao Chen
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang 561113, China
| | - Lili Wang
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang 561113, China.
| | - Zheng Ouyang
- The Second Affiliated Hospital of Guizhou University of Chinese Medicine, Guiyang 550003, China
| | - Weiwei Ouyang
- Department of Thoracic Oncology, the Affiliated Hospital of Guizhou Medical University, Guiyang 550008, China
| | - Chujiao Hu
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang 561113, China.
| | - Jiang Weng
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Ji-Quan Zhang
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang 561113, China.
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Ramaswamy A, Bhargava P, Srinivas S, Kapoor A, Mishra BK, Gupta A, Mandavkar S, Kannan S, Chaugule D, Patil R, Parulekar M, Nashikkar C, Ankathi SK, Kaushal RK, Naughane D, Daddi A, Mer N, Shetty N, Ostwal V. Bevacizumab Erlotinib Switch Maintenance in Chemo-Responsive Advanced Gallbladder and Cholangiocarcinoma (BEER BTC): A Multicenter, Open-Label, Randomized, Phase II Trial. J Clin Oncol 2024; 42:3218-3227. [PMID: 39102628 DOI: 10.1200/jco.23.02420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 03/21/2024] [Accepted: 04/17/2024] [Indexed: 08/07/2024] Open
Abstract
PURPOSE Patients with chemotherapy-responsive advanced biliary tract cancers (BTCs) are usually observed after 6 months of gemcitabine-based therapy. There is limited prospective evidence for maintenance strategies after chemotherapy. METHODS This investigator-initiated, open-label, randomized, integrated phase II-III study enrolled adult patients with advanced BTC from two cancer centers in India. Patients with histologically confirmed advanced biliary tract adenocarcinoma who had at least disease stabilization after 6 months of gemcitabine-based chemotherapy were randomly assigned (1:1) to either active surveillance or switch maintenance, which was a combination of bevacizumab 5 mg/kg intravenous once every 21 days plus erlotinib 100 mg once daily. Both arms were continued until disease progression, unacceptable toxicity, or patient decision to withdraw. The primary end point of the phase II component of the trial was investigator-evaluated progression-free survival. This trial is registered with Clinical Trials Registry of India (CTRI/2019/05/019323I). RESULTS From May 2021 to November 2022, 98 patients were randomly assigned to active surveillance (n = 49) or bevacizumab-erlotinib (n = 49). A majority of patients had gallbladder cancer (80%). The median follow-up was 13.4 months. The median progression-free survival was 3.1 months (95% CI, 2.47 to 3.64) in the active surveillance group versus 5.3 months (95% CI, 3.53 to 7.04) in the bevacizumab-erlotinib group (hazard ratio, 0.51 [95% CI, 0.33 to 0·74]; P = .0013). The most common grade 3 class-specific adverse events associated with bevacizumab-erlotinib were acneiform rash 1 (2%) and oral stomatitis 1 (2%) with erlotinib and bleeding 1 (2%) with bevacizumab. CONCLUSION The combination of bevacizumab and erlotinib as switch maintenance improves progression-free survival with an acceptable safety profile compared with active surveillance in patients with advanced BTCs in this phase II study. The trial moves on to the phase III component to evaluate improvement in overall survival.
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Affiliation(s)
- Anant Ramaswamy
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Prabhat Bhargava
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Sujay Srinivas
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Akhil Kapoor
- Department of Medical Oncology, Homi Bhabha Cancer Hospital, Varanasi, India
| | - Bal Krishna Mishra
- Department of Medical Oncology, Homi Bhabha Cancer Hospital, Varanasi, India
| | - Anuj Gupta
- Department of Medical Oncology, Homi Bhabha Cancer Hospital, Varanasi, India
| | - Sarika Mandavkar
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Sadhana Kannan
- Department of Statistics, Advanced Centre for Treatment, Research and Education in Cancer, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Deepali Chaugule
- CRC, Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Rajshree Patil
- CRC, Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Manali Parulekar
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Chaitali Nashikkar
- Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Suman Kumar Ankathi
- Department of Radiology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Rajiv Kumar Kaushal
- Department of Pathology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Deepali Naughane
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Anuprita Daddi
- Department of Medicine, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Neha Mer
- CRC, Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Nitin Shetty
- Department of Radiology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India
| | - Vikas Ostwal
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, India
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10
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Zhao Y, Yan P, Yang X. Simulating survival data when one subgroup lacks information. J Biopharm Stat 2024; 34:613-625. [PMID: 37496254 DOI: 10.1080/10543406.2023.2236218] [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: 11/11/2021] [Accepted: 07/09/2023] [Indexed: 07/28/2023]
Abstract
In this paper, we aim to show the process of simulating survival data when the distribution of the overall population and one subgroup (called "positive subgroup") as well as the proportion of the subgroup is known, while the distribution of the other subgroup (called "negative subgroup") is unknown. We propose a combination method which generates survival data of the positive subgroup and negative subgroup, respectively, and survival data of the overall population are the combination of the two subgroups. The parameters of the overall population and the positive subgroup need to satisfy certain constraints, otherwise the parameters may lead to contradictions. From simulation, we show that our proposed combination method can reflect the correlation between the test statistics of overall population and positive subgroup, which makes the simulated data more realistic and the results of simulation more reliable. Moreover, for a multiplicity control in trial design, the combination method can help to determine the α splitting strategy between primary endpoints, and is helpful in designs of clinical trials as shown in three applications.
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Affiliation(s)
- Yiqi Zhao
- Guangzhou Culture and Tourism Industry Promotion Center, Guangzhou Tourism Information and Assistance Service Center, Guangzhou, P.R. China
| | - Ping Yan
- Department of Data Science, Shanghai Junshi Biosciences Co., Ltd., Shanghai, P.R. China
| | - Xinfeng Yang
- Department of Statistics and Programming, Jiangsu Hengrui Medicine Co., Ltd., Lianyungang, P.R. China
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11
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Liu Y, Miao L, Chen X, Zhu X, Li Y, He J, Chen P, Dai S, Liu Z, Ma K, Wang N, Zhao Y, Chen N, Song W, Bai R, Cui J, Shu Y. Maintenance therapy with anlotinib after induction therapy with platinum-based chemotherapy for advanced non-small-cell lung cancer: A pooled analysis of 2 single-arm trials. Medicine (Baltimore) 2024; 103:e38459. [PMID: 38968520 PMCID: PMC11224810 DOI: 10.1097/md.0000000000038459] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 05/13/2024] [Indexed: 07/07/2024] Open
Abstract
BACKGROUND Maintenance therapy could significantly improve the prognosis of patients with advanced non-small cell lung cancer (NSCLC) receiving chemotherapy. Anlotinib is effective, tolerable, and convenient in administration as a third-line treatment for NSCLC. This study aimed to evaluate the efficacy and safety of maintenance therapy with anlotinib after platinum-based induction chemotherapy for patients with advanced NSCLC. METHODS This pooled analysis of 2 multicenter, open-label, single-arm, phase 2 clinical trials (ALTER-L014 and ALTER-L011) enrolled patients with locally advanced or metastatic NSCLC and without known sensitive mutations in China between September 2018 and January 2021. The primary outcome was progression-free survival. The secondary outcomes were objective response rate, disease control rate, overall survival, and safety. RESULTS The data of 23 patients were pooled, with 15 from ALTER-L014 and 8 from ALTER-L011. At the cutoff date of June 13, 2021, the median progression-free survival since the start of maintenance therapy was 5.95 (95% confidence interval, 4.30-8.80) months. Nineteen patients had stable disease, 1 had a partial response and 3 had progressive disease. The objective response rate was 4.35%, while disease control rate was 86.96%. The median overall survival of the patients since the start of maintenance therapy was 18.60 (95% confidence interval, 6.87-22.80) months. The incidence of adverse events of grade ≥ 3 was 21.7%. CONCLUSION Anlotinib might offer a new option for maintenance treatment in patients with locally advanced or metastatic NSCLC without known sensitive mutations after standard first-line platinum-based chemotherapy.
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Affiliation(s)
- Yiqian Liu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Liyun Miao
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medicine School, Nanjing, China
| | - Xiao Chen
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Xiaoli Zhu
- Department of Respiratory, Zhongda Hospital, Southeast University, Nanjing, China
| | - Yan Li
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medicine School, Nanjing, China
| | - Jingdong He
- Department of Oncology, Huai’an First Hospital Affiliated to Nanjing Medical University, Huai’an, China
| | - Ping Chen
- Department of Oncology, Yancheng First Hospital Affliated to Nanjing University Medicine School, Yancheng, China
| | - Shengbin Dai
- Department of Oncology, Jiangsu Taizhou People’s Hospital Affiliated to Nanjing Medical University, Taizhou, China
| | - Ziling Liu
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Kewei Ma
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Nanya Wang
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Yuguang Zhao
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Naifei Chen
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Wei Song
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Rilan Bai
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Jiuwei Cui
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Yongqian Shu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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12
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Zhou S, Kishi N, Alerasool P, Rohs NC. Adverse Event Profile of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Non-small Cell Lung Cancer: An Updated Meta-analysis. Target Oncol 2024; 19:547-564. [PMID: 38824269 DOI: 10.1007/s11523-024-01073-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/14/2024] [Indexed: 06/03/2024]
Abstract
BACKGROUND Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remain the frontline standard of care for patients with EGFR-mutant non-small cell lung cancer. An updated toxicity profile of EGFR-TKIs proves valuable in guiding clinical decision making. OBJECTIVE This study comprehensively assessed the risk of EGFR-TKI-related adverse events (AEs) involving different systems/organs. METHODS We systematically searched PubMed, Embase, Web of Science, and Cochrane library for phase III randomized controlled trials comparing EGFR-TKI monotherapy with placebo or chemotherapy in patients with non-small cell lung cancer. The odds ratio (OR) of all-grade and high-grade adverse events (AEs) including dermatologic, gastrointestinal, hematologic, hepatic, and respiratory events was pooled for a meta-analysis. Subgroup analyses based on the control arm (placebo or chemotherapy) and individual EGFR-TKIs (erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib) were conducted. RESULTS Thirty-four randomized controlled trials comprising 15,887 patients were included. The pooled OR showed EGFR-TKIs were associated with a significantly increased risk of all-grade dermatologic AEs including paronychia, pruritus, rash, skin exfoliation, and skin fissures, gastrointestinal AEs including abdominal pain, diarrhea, dyspepsia, mouth ulceration, and stomatitis, hepatic AEs including elevated alanine aminotransferase and aspartate aminotransferase, and respiratory AEs including epistaxis, interstitial lung disease and rhinorrhea. Furthermore, a significantly increased risk of high-grade rash (OR 7.83, 95% confidence interval [CI] 5.11, 12.00), diarrhea (OR 2.10, 95% CI 1.44, 3.05), elevated alanine aminotransferase (OR 3.93, 95% CI 1.71, 9.03), elevated aspartate aminotransferase (OR 3.22, 95% CI 1.05, 9.92) and interstitial lung disease (OR 2.35, 95% CI 1.38, 4.01) was observed in patients receiving EGFR-TKIs. When stratified by individual EGFR-TKIs, gefitinib showed a significant association with all-grade and high-grade hepatotoxicity and interstitial lung disease. CONCLUSIONS Epidermal growth factor receptor tyrosine kinase inhibitors were associated with a significantly increased risk of various types of AEs. Clinicians should be vigilant about the risks of these EGFR-TKI-related AEs, particularly for severe hepatotoxicity and interstitial lung disease, to facilitate early detection and proper management.
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Affiliation(s)
- Susu Zhou
- Department of Medicine, Icahn School of Medicine at Mount Sinai, 281 First Avenue, New York, NY, 10003, USA.
| | - Noriko Kishi
- Department of Radiation Oncology and Image-Applied Therapy, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Parissa Alerasool
- Division of Hematology/Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- New York Medical College, Valhalla, NY, USA
| | - Nicholas C Rohs
- Center for Thoracic Oncology, Tisch Cancer Institute and Icahn School of Medicine at Mount Sinai, New York, NY, USA
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13
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Lai X, Zeng J, Xiao Z, Xiao J. Efficacy and safety of EGFR-TKIs for non-small cell lung cancer: A meta-analysis of randomized controlled clinical trials. Medicine (Baltimore) 2024; 103:e38277. [PMID: 38847673 PMCID: PMC11155537 DOI: 10.1097/md.0000000000038277] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 04/26/2024] [Indexed: 06/10/2024] Open
Abstract
BACKGROUND We conducted this meta-analysis based on updated literature and research to compare the efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) as treatments for patients with non-small cell lung cancer (NSCLC). METHODS A literature search was conducted using PubMed, Embase, Medline and Web of Science databases to perform a systematic literature search based on random control trials. In these articles, EGFR-TKIs were compared with placebos, chemotherapy, or whole-brain irradiation as treatments for NSCLC. In this research, a meta-analysis of the literature was performed to produce a combined risk ratio (RR) with a 95% confidence interval (CI) for progression-free survival (PFS), overall survival (OS), and adverse events. The data were synthesized with Review Manager 5.3 software, which was used to manage the process. RESULTS There were 15 random control trials included in the study, involving 4249 patients in total. There was evidence that EGFR-TKIs can significantly prolong OS (RR: 0.87, 95% CI: 0.75-1) and PFS (RR: 0.75, 95% CI: 0.66-0.86) in NSCLC patients. There was an increase in the incidence of adverse events after treatment with EGFR-TKI, including diarrhea (RR: 0.18, 95% CI: 0.10-0.26), infection (RR: 0.09, 95% CI: 0.02-0.16), and rash (RR: 0.37, 95% CI: 0.22-0.51). CONCLUSIONS It has been shown that EGFR-TKIs prolong OS and PFS in patients with NSCLC. NSCLC patients may benefit from EGFR-TKIs as an important treatment option in order to prolong their survival.
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Affiliation(s)
- Xiaoming Lai
- Pathological teaching and research office, Gannan Health Vocational College, Ganzhou, Jiangxi, China
| | - Jinlin Zeng
- Pathology department, Ganzhou People’s Hospital, Ganzhou, Jiangxi, China
| | - Zhijun Xiao
- Clinical medicine, Inner Mongolia University of Science and Technology Baotou Medical College, Baotou, Inner Mongolia, China
| | - Junlan Xiao
- Pathology department, Ganzhou People’s Hospital, Ganzhou, Jiangxi, China
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14
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Gits HC, Khosravi Flanigan MA, Kapplinger JD, Reisenauer JS, Eiken PW, Breen WG, Vu LH, Welch BT, Harmsen WS, Day CN, Olivier KR, Park SS, Garces YI, Hallemeier CL, Merrell KW, Ashman JB, Schild SE, Grams MP, Lucido JJ, Shen KR, Cassivi SD, Wigle D, Nichols FC, Blackmon S, Tapias LF, Callstrom MR, Owen D. Sublobar Resection, Stereotactic Body Radiation Therapy, and Percutaneous Ablation Provide Comparable Outcomes for Lung Metastasis-Directed Therapy. Chest 2024; 165:1247-1259. [PMID: 38103730 DOI: 10.1016/j.chest.2023.12.013] [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: 04/11/2023] [Revised: 11/29/2023] [Accepted: 12/04/2023] [Indexed: 12/19/2023] Open
Abstract
BACKGROUND Prolonged survival of patients with metastatic disease has furthered interest in metastasis-directed therapy (MDT). RESEARCH QUESTION There is a paucity of data comparing lung MDT modalities. Do outcomes among sublobar resection (SLR), stereotactic body radiation therapy (SBRT), and percutaneous ablation (PA) for lung metastases vary in terms of local control and survival? STUDY DESIGN AND METHODS Medical records of patients undergoing lung MDT at a single cancer center between January 2015 and December 2020 were reviewed. Overall survival, local progression, and toxicity outcomes were collected. Patient and lesion characteristics were used to generate multivariable models with propensity weighted analysis. RESULTS Lung MDT courses (644 total: 243 SLR, 274 SBRT, 127 PA) delivered to 511 patients were included with a median follow-up of 22 months. There were 47 local progression events in 45 patients, and 159 patients died. Two-year overall survival and local progression were 80.3% and 63.3%, 83.8% and 9.6%, and 4.1% and 11.7% for SLR, SBRT, and PA, respectively. Lesion size per 1 cm was associated with worse overall survival (hazard ratio, 1.24; P = .003) and LP (hazard ratio, 1.50; P < .001). There was no difference in overall survival by modality. Relative to SLR, there was no difference in risk of local progression with PA; however, SBRT was associated with a decreased risk (hazard ratio, 0.26; P = .023). Rates of severe toxicity were low (2.1%-2.6%) and not different among groups. INTERPRETATION This study performs a propensity weighted analysis of SLR, SBRT, and PA and shows no impact of lung MDT modality on overall survival. Given excellent local control across MDT options, a multidisciplinary approach is beneficial for patient triage and longitudinal management.
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Affiliation(s)
- Hunter C Gits
- Departments of Radiation Oncology, Mayo Clinic, Rochester, MN
| | | | | | | | | | - William G Breen
- Departments of Radiation Oncology, Mayo Clinic, Rochester, MN
| | - Linh H Vu
- Pulmonary and Critical Care Medicine, and Biostatistics and Health Sciences Research, Mayo Clinic, Rochester, MN
| | | | - William S Harmsen
- Pulmonary and Critical Care Medicine, and Biostatistics and Health Sciences Research, Mayo Clinic, Rochester, MN
| | - Courtney N Day
- Pulmonary and Critical Care Medicine, and Biostatistics and Health Sciences Research, Mayo Clinic, Rochester, MN
| | | | - Sean S Park
- Departments of Radiation Oncology, Mayo Clinic, Rochester, MN
| | | | | | | | | | | | - Michael P Grams
- Departments of Radiation Oncology, Mayo Clinic, Rochester, MN
| | - J John Lucido
- Departments of Radiation Oncology, Mayo Clinic, Rochester, MN
| | | | | | | | | | | | | | | | - Dawn Owen
- Departments of Radiation Oncology, Mayo Clinic, Rochester, MN.
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15
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Zhu Z, Li J, Shen S, Al-Furas H, Li S, Tong Y, Li Y, Zeng Y, Feng Q, Chen K, Ma N, Zhou F, Zhang Z, Li Z, Pang J, Ding K, Xu F. Targeting EGFR degradation by autophagosome degraders. Eur J Med Chem 2024; 270:116345. [PMID: 38564826 DOI: 10.1016/j.ejmech.2024.116345] [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: 01/27/2024] [Revised: 03/04/2024] [Accepted: 03/17/2024] [Indexed: 04/04/2024]
Abstract
Several generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been developed for the treatment of non-small cell lung cancer (NSCLC) in clinic. However, emerging drug resistance mediated by new EGFR mutations or activations by pass, leads to malignant progression of NSCLC. Proteolysis targeting chimeras (PROTACs) have been utilized to overcome the drug resistance acquired by mutant EGFR, newly potent and selective degraders are still need to be developed for clinical applications. Herein, we developed autophagosome-tethering compounds (ATTECs) in which EGFR can be anchored to microtubule-associated protein-1 light chain-3B (LC3B) on the autophagosome with the assistance of the LC3 ligand GW5074. A series of EGFR-ATTECs have been designed and synthesized. Biological evaluations showed that these compounds could degrade EGFR and exhibited moderate inhibitory effects on certain NSCLC cell lines. The ATTEC 12c potently induced the degradation of EGFR with a DC50 value of 0.98 μM and a Dmax value of 81% in HCC827 cells. Mechanistic exploration revealed that the lysosomal pathway was mainly involved in this degradation. Compound 12c also exhibited promising inhibitory activity, as well as degradation efficiency in vivo. Our study highlights that EGFR-ATTECs could be developed as a new expandable EGFR degradation tool and also reveals a novel potential therapeutic strategy to prevent drug resistance acquired EGFR mutations.
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Affiliation(s)
- ZhongFeng Zhu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Jiaying Li
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Shujun Shen
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Hawaa Al-Furas
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Shengrong Li
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Yichen Tong
- School of Chemistry, Sun Yat-sen University, Guangzhou, 510006, China
| | - Yi Li
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Yucheng Zeng
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Qianyi Feng
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Kaiyue Chen
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Nan Ma
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Fengtao Zhou
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.
| | - Zhang Zhang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Zhengqiu Li
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China
| | - Jiyan Pang
- School of Chemistry, Sun Yat-sen University, Guangzhou, 510006, China.
| | - Ke Ding
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China; State Key Laboratory of Chemical Biology, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China.
| | - Fang Xu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.
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16
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Parera Roig M, Colomé DC, Colomer GB, Sardo EG, Tournour MA, Fernández SG, Ominetti AI, Juvanteny EP, Polo JLM, Jobal DB, Espejo-Herrera N. Evolution of Diagnoses, Survival, and Costs of Oncological Medical Treatment for Non-Small-Cell Lung Cancer over 20 Years in Osona, Catalonia. Curr Oncol 2024; 31:2145-2157. [PMID: 38668062 PMCID: PMC11049066 DOI: 10.3390/curroncol31040159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 04/04/2024] [Accepted: 04/06/2024] [Indexed: 04/28/2024] Open
Abstract
Non-small-cell lung cancer (NSCLC) has experienced several diagnostic and therapeutic changes over the past two decades. However, there are few studies conducted with real-world data regarding the evolution of the cost of these new drugs and the corresponding changes in the survival of these patients. We collected data on patients diagnosed with NSCLC from the tumor registry of the University Hospital of Vic from 2002 to 2021. We analyzed the epidemiological and pathological characteristics of these patients, the diverse oncological treatments administered, and the survival outcomes extending at least 18 months post-diagnosis. We also collected data on pharmacological costs, aligning them with the treatments received by each patient to determine the cost associated with individualized treatments. Our study included 905 patients diagnosed with NSCLC. We observed a dynamic shift in histopathological subtypes from squamous carcinoma in the initial years to adenocarcinoma. Regarding the treatment approach, the use of chemotherapy declined over time, replaced by immunotherapy, while molecular therapy showed relative stability. An increase in survival at 18 months after diagnosis was observed in patients with advanced stages over the most recent years of this study, along with the advent of immunotherapy. Mean treatment costs per patient ranged from EUR 1413.16 to EUR 22,029.87 and reached a peak of EUR 48,283.80 in 2017 after the advent of immunotherapy. This retrospective study, based on real-world data, documents the evolution of pathological characteristics, survival rates, and medical treatment costs for NSCLC over the last two decades. After the introduction of immunotherapy, patients in advanced stages showed an improvement in survival at 18 months, coupled with an increase in treatment costs.
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Affiliation(s)
- Marta Parera Roig
- Oncohematology Unit, Consorci Hospitalari de Vic (University Hospital of Vic), 08500 Vic, Spain; (E.G.S.); (M.A.T.); (S.G.F.); (A.I.O.)
- School of Medicine, University of Vic-Central University of Catalonia (UVIC-UCC), 08500 Vic, Spain; (D.B.J.); (N.E.-H.)
- Doctoral College, Medicine and Biomedical Sciences, University of Vic-Central University of Catalonia (UVic-UCC), 08500 Vic, Spain
- Mechanisms of Disease Laboratory Research Group (MoD Lab), IRIS-CC, University of Vic-Central University of Catalonia (UVic-UCC), 08500 Vic, Spain
| | - David Compte Colomé
- Planning and Information Systems Department, Consorci Hospitalari de Vic (University Hospital of Vic), 08500 Vic, Spain;
| | - Gemma Basagaña Colomer
- Pharmacy Department, Consorci Hospitalari de Vic (University Hospital of Vic), 08500 Vic, Spain;
| | - Emilia Gabriela Sardo
- Oncohematology Unit, Consorci Hospitalari de Vic (University Hospital of Vic), 08500 Vic, Spain; (E.G.S.); (M.A.T.); (S.G.F.); (A.I.O.)
- School of Medicine, University of Vic-Central University of Catalonia (UVIC-UCC), 08500 Vic, Spain; (D.B.J.); (N.E.-H.)
| | - Mauricio Alejandro Tournour
- Oncohematology Unit, Consorci Hospitalari de Vic (University Hospital of Vic), 08500 Vic, Spain; (E.G.S.); (M.A.T.); (S.G.F.); (A.I.O.)
| | - Silvia Griñó Fernández
- Oncohematology Unit, Consorci Hospitalari de Vic (University Hospital of Vic), 08500 Vic, Spain; (E.G.S.); (M.A.T.); (S.G.F.); (A.I.O.)
| | - Arturo Ivan Ominetti
- Oncohematology Unit, Consorci Hospitalari de Vic (University Hospital of Vic), 08500 Vic, Spain; (E.G.S.); (M.A.T.); (S.G.F.); (A.I.O.)
| | - Emma Puigoriol Juvanteny
- Epidemiology Department, Consorci Hospitalari de Vic (University Hospital of Vic), 08500 Vic, Spain;
- Multidisciplinary Inflammation Research Group (MIRG), IRIS-CC, 08500 Vic, Spain
| | - José Luis Molinero Polo
- Pathology Department, Consorci Hospitalari de Vic (University Hospital of Vic), 08500 Vic, Spain;
| | - Daniel Badia Jobal
- School of Medicine, University of Vic-Central University of Catalonia (UVIC-UCC), 08500 Vic, Spain; (D.B.J.); (N.E.-H.)
- Pathology Department, Consorci Hospitalari de Vic (University Hospital of Vic), 08500 Vic, Spain;
| | - Nadia Espejo-Herrera
- School of Medicine, University of Vic-Central University of Catalonia (UVIC-UCC), 08500 Vic, Spain; (D.B.J.); (N.E.-H.)
- Multidisciplinary Inflammation Research Group (MIRG), IRIS-CC, 08500 Vic, Spain
- Pathology Department, Consorci Hospitalari de Vic (University Hospital of Vic), 08500 Vic, Spain;
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AbdulMajeed J, Khatib M, Dulli M, Sioufi S, Al-Khulaifi A, Stone J, Furuya-Kanamori L, Onitilo AA, Doi SAR. Use of conditional estimates of effect in cancer epidemiology: An application to lung cancer treatment. Cancer Epidemiol 2024; 88:102521. [PMID: 38160570 DOI: 10.1016/j.canep.2023.102521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 12/06/2023] [Accepted: 12/22/2023] [Indexed: 01/03/2024]
Abstract
BACKGROUND In oncology clinical trials, there is the assumption that randomization sufficiently balances confounding covariates and therefore average treatment effects are usually reported. This paper explores the wider benefits provided by conditioning on covariates for reasons other than mitigation of confounding. METHODS We reanalyzed the data from primary randomized controlled trials listed in two meta-analyses to explore the significance of conditioning on smoking status in terms of the effect magnitude of treatment on progression free survival in non-small cell lung cancer. RESULTS The reanalysis revealed that conditioning on smoking status using sub-group analyses provided the closest empiric estimate of individual treatment effect based on smoking status and significantly reduced the heterogeneity of treatment effect observed across studies. In addition, smoking status was determined to be a modifier of the effect of treatment. CONCLUSION Conditioning on prognostic covariates in randomized trials in oncology helps generate the closest empiric estimates of individual treatment benefit, addresses heterogeneity due to varying covariate distributions across trials and facilitates future decision making as well as evidence synthesis. Conditioning using sub-group analyses also allows examination for effect modification in meta-analysis.
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Affiliation(s)
- Jazeel AbdulMajeed
- Department of Population Medicine, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Malkan Khatib
- Department of Population Medicine, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Mohamad Dulli
- Department of Medicine, Hamad General Hospital, Doha, Qatar
| | | | - Azhar Al-Khulaifi
- Department of Population Medicine, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Jennifer Stone
- Joanna Briggs Institute, Faculty of Health and Medical Sciences, University of Adelaide, Australia
| | - Luis Furuya-Kanamori
- UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Herston 4029, Australia
| | - Adedayo A Onitilo
- Department of Oncology, Marshfield Clinic Health System, Marshfield, WI, USA
| | - Suhail A R Doi
- Department of Population Medicine, College of Medicine, QU Health, Qatar University, Doha, Qatar.
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Ortiz Carrodeguas RA, Lorenzo Monteagudo G, Guerra Chaviano PP, Álvarez Montané I, Salomón Saldívar EE, Lobaina Lambert L, Camacho Sosa K, Bermúdez Pino R, Blanco Mustelier P, Valdés Rodríguez E, González Piloto S, Guerra de la Vega A, Valdés Sánchez L, Montes De Santis A, Parra Zabala J, Viada González C, Calvo Aguilera N, Saavedra Hernández D, Santos Morales O, Crombet Ramos T. Safety and effectiveness of CIMAvax-EGF administered in community polyclinics. Front Oncol 2024; 13:1287902. [PMID: 38304035 PMCID: PMC10830698 DOI: 10.3389/fonc.2023.1287902] [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: 09/18/2023] [Accepted: 12/19/2023] [Indexed: 02/03/2024] Open
Abstract
In spite of the advances in immunotherapy and targeted therapies, lung cancer continues to be the leading cause of cancer-related death. The epidermal growth factor receptor is an established target for non-small cell lung cancer (NSCLC), and its overactivation by the ligands can induce accelerated proliferation, angiogenesis, and metastasis as well as proinflammatory or immunosuppressive signals. CIMAvax-EGF is an epidermal growth factor (EGF)-depleting immunotherapy that is approved for the treatment of NSCLC patients in Cuba. The study was designed as a phase IV trial to characterize the safety and effectiveness of CIMAvax-EGF in advanced NSCLC patients treated in 119 community polyclinics and 24 hospitals. CIMAvax-EGF treatment consisted of four bi-weekly doses followed by monthly boosters. Overall, 741 NSCLC patients ineligible for further cancer-specific treatment were enrolled. CIMAvax-EGF was safe, and the most common adverse events consisted of mild-to-moderate injection site reactions, fever, chills, tremors, and headache. For patients completing the loading doses, the median survival was 9.9 months. For individuals achieving at least stable disease to the frontline and completing vaccination induction, the median survival was 12 months. Most of the functional activities and symptoms evaluated through the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire improved over time. In conclusion, this real-world trial demonstrated that CIMAvax-EGF was safe and effective in patients who were vaccinated in the maintenance scenario. A larger effect was seen in subjects with poor prognosis like those with squamous tumors and high EGF levels. Remarkably, this community-based intervention was very important because it demonstrated the feasibility of treating advanced lung cancer patients with active immunotherapy in primary care institutions. In addition to CIMAvax-EGF, patients received supportive care at the community clinic. Vaccine administration by the family doctors at the polyclinics reduced the patients' burden on the medical oncology services that continued providing chemotherapy and other complex therapies. We conclude that community polyclinics constitute the optimal scenario for administering those cancer vaccines that are safe and require prolonged maintenance in patients with advanced cancer, despite the continuous deterioration of their general condition. Clinical trial registration https://rpcec.sld.cu/trials/RPCEC00000205-En, identifier RPCEC00000205.
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Affiliation(s)
| | | | | | | | | | | | | | - Raúl Bermúdez Pino
- “Mario Gutiérrez Ardaya” Polyclinic, Family Medicine Department, Holguín, Cuba
| | | | - Elba Valdés Rodríguez
- “Octavio de la Concepción y la Pedraja” Polyclinic, Family Medicine Department. Santa Clara, Villa Clara, Cuba
| | | | | | | | | | - Jenelly Parra Zabala
- National Coordinating Center for Clinical Trials, Clinical Research Department, Havana, Cuba
| | | | - Nadia Calvo Aguilera
- National Coordinating Center for Clinical Trials, Clinical Research Department, Havana, Cuba
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Shaban N, Kamashev D, Emelianova A, Buzdin A. Targeted Inhibitors of EGFR: Structure, Biology, Biomarkers, and Clinical Applications. Cells 2023; 13:47. [PMID: 38201251 PMCID: PMC10778338 DOI: 10.3390/cells13010047] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 12/20/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024] Open
Abstract
Members of the EGFR family of tyrosine kinase receptors are major regulators of cellular proliferation, differentiation, and survival. In humans, abnormal activation of EGFR is associated with the development and progression of many cancer types, which makes it an attractive target for molecular-guided therapy. Two classes of EGFR-targeted cancer therapeutics include monoclonal antibodies (mAbs), which bind to the extracellular domain of EGFR, and tyrosine kinase inhibitors (TKIs), which mostly target the intracellular part of EGFR and inhibit its activity in molecular signaling. While EGFR-specific mAbs and three generations of TKIs have demonstrated clinical efficacy in various settings, molecular evolution of tumors leads to apparent and sometimes inevitable resistance to current therapeutics, which highlights the need for deeper research in this field. Here, we tried to provide a comprehensive and systematic overview of the rationale, molecular mechanisms, and clinical significance of the current EGFR-targeting drugs, highlighting potential candidate molecules in development. We summarized the underlying mechanisms of resistance and available personalized predictive approaches that may lead to improved efficacy of EGFR-targeted therapies. We also discuss recent developments and the use of specific therapeutic strategies, such as multi-targeting agents and combination therapies, for overcoming cancer resistance to EGFR-specific drugs.
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Affiliation(s)
- Nina Shaban
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia; (D.K.); (A.B.)
- Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia
| | - Dmitri Kamashev
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia; (D.K.); (A.B.)
- Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia
- Institute of Personalized Oncology, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia
| | - Aleksandra Emelianova
- World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov First Moscow State Medical University, Moscow 119991, Russia;
| | - Anton Buzdin
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia; (D.K.); (A.B.)
- Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia
- Institute of Personalized Oncology, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia
- PathoBiology Group, European Organization for Research and Treatment of Cancer (EORTC), 1200 Brussels, Belgium
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20
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Mo Z, Ye M, He H, Huang X, Guo W, Zhao Z, Li Y, Wei S. Influence of Smoking Habits on the Efficacy of EGFR-TKI Therapy in Patients with Advanced NSCLC: A Systematic Review and Meta-Analysis. Clin Med Insights Oncol 2023; 17:11795549231215968. [PMID: 38107371 PMCID: PMC10722912 DOI: 10.1177/11795549231215968] [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: 05/16/2023] [Accepted: 10/24/2023] [Indexed: 12/19/2023] Open
Abstract
Background Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are considered as the first-line treatment for advanced EGFR mutation-positive non-small cell lung cancer (NSCLC). We aimed to analyze the efficacy of EGFR-TKIs treatment in patients with advanced NSCLC of different smoking habits. Methods We conducted a search for meta-analyses and systematic reviews on the PubMed, MEDLINE, Embase, and the Cochrane Library to address this knowledge gap. Patients were divided into 2 groups: (1) experimental group: treated with EGFR-TKIs or EGFR-TKIs combined with chemotherapy, immunotherapy, antiangiogenesis, radiotherapy and (2) control group: treated with chemotherapy. Progressive-free survival (PFS) and total survival (OS) were adopted for evaluating the efficacy of EGFR-TKIs between experimental group and control group. Results Eleven studies including 6760 patients were included in the meta-analysis. The results showed that smoking (including previous and current smoking) significantly reduces the PFS and OS in comparison to non-smoking group in the treatment of NSCLC with EGFR-TKIs. In addition, EGFR-TKIs combined with anti-vascular endothelial growth factor therapy can reduce the risk of disease progression in smokers. Conclusions Our study indicated that smoking significantly reduced the PFS and OS in comparison to non-smoking group in the treatment of NSCLC with EGFR-TKIs.
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Affiliation(s)
- Zexun Mo
- Department of Pulmonary and Critical Care Medicine, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Meifeng Ye
- Department of Pulmonary and Critical Care Medicine, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Hua He
- Department of Pulmonary and Critical Care Medicine, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Xiaomei Huang
- Department of Pulmonary and Critical Care Medicine, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Weihong Guo
- Department of Pulmonary and Critical Care Medicine, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Ziwen Zhao
- Department of Pulmonary and Critical Care Medicine, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Yujun Li
- Department of Pulmonary and Critical Care Medicine, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Shuquan Wei
- Department of Pulmonary and Critical Care Medicine, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
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21
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Wells L, Qin A. Treatment of Non-Small Cell Lung Cancer with Atypical EGFR Mutations. Curr Treat Options Oncol 2023; 24:1802-1814. [PMID: 38095779 DOI: 10.1007/s11864-023-01159-z] [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] [Accepted: 11/21/2023] [Indexed: 01/11/2024]
Abstract
OPINION STATEMENT EGFR tyrosine kinase inhibitors (TKI) should always be considered when treating advanced/metastatic non-small cell lung cancer (NSCLC) with atypical EGFR mutations. The first choice of TKI depends on the specific mutation(s) present and its effect on structure and function of the EGFR protein. Afatinib is the only EGFR TKI currently FDA approved for atypical EGFR mutations and has the strongest data to support its use in PACC mutations, a subgroup of atypical EGFR mutations which includes G719X and S7681. Dacomitinib may also be an option for these mutations given similar efficacy to afatinib. In contrast, for classical-like mutations such as L861Q, osimertinib should be considered the first choice given that their behavior mimics that of the classical mutations exon 19 deletion and L858R. Osimertinib should also be utilized in the setting of a concurrent T790M mutation. Superior CNS penetrance and well managed toxicity profile may also be reasons to consider osimertinib. Given that the choice of TKI may depend on the specific mutation, it is crucial that every patient diagnosed with NSCLC undergo comprehensive sequencing to identify these mutations.
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Affiliation(s)
- Leah Wells
- Department of Internal Medicine, Division of Hematology-Oncology, University of Michigan, 1500 E. Medical Center Drive, SPC 5848, Med Inn C349, Ann Arbor, MI, 48103, USA
| | - Angel Qin
- Department of Internal Medicine, Division of Hematology-Oncology, University of Michigan, 1500 E. Medical Center Drive, SPC 5848, Med Inn C349, Ann Arbor, MI, 48103, USA.
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Santi MD, Zhang M, Liu N, Viet CT, Xie T, Jensen DD, Amit M, Pan H, Ye Y. Repurposing EGFR Inhibitors for Oral Cancer Pain and Opioid Tolerance. Pharmaceuticals (Basel) 2023; 16:1558. [PMID: 38004424 PMCID: PMC10674507 DOI: 10.3390/ph16111558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 10/24/2023] [Accepted: 10/27/2023] [Indexed: 11/26/2023] Open
Abstract
Oral cancer pain remains a significant public health concern. Despite the development of improved treatments, pain continues to be a debilitating clinical feature of the disease, leading to reduced oral mobility and diminished quality of life. Opioids are the gold standard treatment for moderate-to-severe oral cancer pain; however, chronic opioid administration leads to hyperalgesia, tolerance, and dependence. The aim of this review is to present accumulating evidence that epidermal growth factor receptor (EGFR) signaling, often dysregulated in cancer, is also an emerging signaling pathway critically involved in pain and opioid tolerance. We presented preclinical and clinical data to demonstrate how repurposing EGFR inhibitors typically used for cancer treatment could be an effective pharmacological strategy to treat oral cancer pain and to prevent or delay the development of opioid tolerance. We also propose that EGFR interaction with the µ-opioid receptor and glutamate N-methyl-D-aspartate receptor could be two novel downstream mechanisms contributing to pain and morphine tolerance. Most data presented here support that repurposing EGFR inhibitors as non-opioid analgesics in oral cancer pain is promising and warrants further research.
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Affiliation(s)
- Maria Daniela Santi
- Translational Research Center, College of Dentistry, New York University, New York, NY 10010, USA; (M.D.S.); (M.Z.); (N.L.); (D.D.J.)
- Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY 10010, USA
| | - Morgan Zhang
- Translational Research Center, College of Dentistry, New York University, New York, NY 10010, USA; (M.D.S.); (M.Z.); (N.L.); (D.D.J.)
- Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY 10010, USA
| | - Naijiang Liu
- Translational Research Center, College of Dentistry, New York University, New York, NY 10010, USA; (M.D.S.); (M.Z.); (N.L.); (D.D.J.)
- Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY 10010, USA
| | - Chi T. Viet
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Loma Linda University, Loma Linda, CA 92350, USA;
| | - Tongxin Xie
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (T.X.); (M.A.)
| | - Dane D. Jensen
- Translational Research Center, College of Dentistry, New York University, New York, NY 10010, USA; (M.D.S.); (M.Z.); (N.L.); (D.D.J.)
- Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY 10010, USA
| | - Moran Amit
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (T.X.); (M.A.)
| | - Huilin Pan
- Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Yi Ye
- Translational Research Center, College of Dentistry, New York University, New York, NY 10010, USA; (M.D.S.); (M.Z.); (N.L.); (D.D.J.)
- Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY 10010, USA
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Sakanyan V, Iradyan N, Alves de Sousa R. Targeted Strategies for Degradation of Key Transmembrane Proteins in Cancer. BIOTECH 2023; 12:57. [PMID: 37754201 PMCID: PMC10526213 DOI: 10.3390/biotech12030057] [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: 07/05/2023] [Revised: 07/26/2023] [Accepted: 07/30/2023] [Indexed: 09/28/2023] Open
Abstract
Targeted protein degradation is an attractive technology for cancer treatment due to its ability to overcome the unpredictability of the small molecule inhibitors that cause resistance mutations. In recent years, various targeted protein degradation strategies have been developed based on the ubiquitin-proteasome system in the cytoplasm or the autophagy-lysosomal system during endocytosis. In this review, we describe and compare technologies for the targeted inhibition and targeted degradation of the epidermal growth factor receptor (EGFR), one of the major proteins responsible for the onset and progression of many types of cancer. In addition, we develop an alternative strategy, called alloAUTO, based on the binding of new heterocyclic compounds to an allosteric site located in close proximity to the EGFR catalytic site. These compounds cause the targeted degradation of the transmembrane receptor, simultaneously activating both systems of protein degradation in cells. Damage to the EGFR signaling pathways promotes the inactivation of Bim sensor protein phosphorylation, which leads to the disintegration of the cytoskeleton, followed by the detachment of cancer cells from the extracellular matrix, and, ultimately, to cancer cell death. This hallmark of targeted cancer cell death suggests an advantage over other targeted protein degradation strategies, namely, the fewer cancer cells that survive mean fewer chemotherapy-resistant mutants appear.
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Affiliation(s)
- Vehary Sakanyan
- Faculté de Pharmacie, Université de Nantes, 44035 Nantes, France
- ProtNeteomix, 29 rue de Provence, 44700 Orvault, France
| | - Nina Iradyan
- Institute of Fine Organic Chemistry after A. Mnjoyan, National Academy of Sciences of the Republic of Armenia, Yerevan 0014, Armenia;
| | - Rodolphe Alves de Sousa
- Faculté des Sciences Fondamentales et Biomédicales, Université Paris Descartes, UMR 8601, CBMIT, 75006 Paris, France;
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Pathak S, Zajac KK, Annaji M, Govindarajulu M, Nadar RM, Bowen D, Babu RJ, Dhanasekaran M. Clinical outcomes of chemotherapy in cancer patients with different ethnicities. Cancer Rep (Hoboken) 2023; 6 Suppl 1:e1830. [PMID: 37150853 PMCID: PMC10440845 DOI: 10.1002/cnr2.1830] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 04/18/2023] [Accepted: 04/21/2023] [Indexed: 05/09/2023] Open
Abstract
BACKGROUND Choosing the most effective chemotherapeutic agent with safest side effect profile is a common challenge in cancer treatment. Although there are standardized chemotherapy protocols in place, protocol changes made after extensive clinical trials demonstrate significant improvement in the efficacy and tolerability of certain drugs. The pharmacokinetics, pharmacodynamics, and tolerance of anti-cancer medications are all highly individualized. A driving force behind these differences lies within a person's genetic makeup. RECENT FINDINGS Pharmacogenomics, the study of how an individual's genes impact the processing and action of a drug, can optimize drug responsiveness and reduce toxicities by creating a customized medication regimen. However, these differences are rarely considered in the initial determination of standardized chemotherapeutic protocols and treatment algorithms. Because pharmacoethnicity is influenced by both genetic and nongenetic variables, clinical data highlighting disparities in the frequency of polymorphisms between different ethnicities is steadily growing. Recent data suggests that ethnic variations in the expression of allelic variants may result in different pharmacokinetic properties of the anti-cancer medication. In this article, the clinical outcomes of various chemotherapy classes in patients of different ethnicities were reviewed. CONCLUSION Genetic and nongenetic variables contribute to the interindividual variability in response to chemotherapeutic drugs. Considering pharmacoethnicity in the initial determination of standard chemotherapeutic protocols and treatment algorithms can lead to better clinical outcomes of patients of different ethnicities.
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Affiliation(s)
- Suhrud Pathak
- Department of Drug Discovery and Development, Harrison College of PharmacyAuburn UniversityAuburnAlabamaUSA
| | - Kelsee K. Zajac
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical SciencesUniversity of ToledoToledoOhioUSA
| | - Manjusha Annaji
- Department of Drug Discovery and Development, Harrison College of PharmacyAuburn UniversityAuburnAlabamaUSA
| | - Manoj Govindarajulu
- Department of Drug Discovery and Development, Harrison College of PharmacyAuburn UniversityAuburnAlabamaUSA
| | - Rishi M. Nadar
- Department of Drug Discovery and Development, Harrison College of PharmacyAuburn UniversityAuburnAlabamaUSA
| | - Dylan Bowen
- Department of Drug Discovery and Development, Harrison College of PharmacyAuburn UniversityAuburnAlabamaUSA
| | - R. Jayachandra Babu
- Department of Drug Discovery and Development, Harrison College of PharmacyAuburn UniversityAuburnAlabamaUSA
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Lefebvre C, Pellizzari S, Bhat V, Jurcic K, Litchfield DW, Allan AL. Involvement of the AKT Pathway in Resistance to Erlotinib and Cabozantinib in Triple-Negative Breast Cancer Cell Lines. Biomedicines 2023; 11:2406. [PMID: 37760847 PMCID: PMC10525382 DOI: 10.3390/biomedicines11092406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/14/2023] [Accepted: 08/26/2023] [Indexed: 09/29/2023] Open
Abstract
Resistance to protein tyrosine kinase inhibitors (TKIs) presents a significant challenge in therapeutic target development for cancers such as triple-negative breast cancer (TNBC), where conventional therapies are ineffective at combatting systemic disease. Due to increased expression, the receptor tyrosine kinases EGFR (epidermal growth factor receptor) and c-Met are potential targets for treatment. However, targeted anti-EGFR and anti-c-Met therapies have faced mixed results in clinical trials due to acquired resistance. We hypothesize that adaptive responses in regulatory kinase networks within the EGFR and c-Met signaling axes contribute to the development of acquired erlotinib and cabozantinib resistance. To test this, we developed two separate models for cabozantinib and erlotinib resistance using the MDA-MB-231 and MDA-MB-468 cell lines, respectively. We observed that erlotinib- or cabozantinib-resistant cell lines demonstrate enhanced cell proliferation, migration, invasion, and activation of EGFR or c-Met downstream signaling (respectively). Using a SILAC (Stable Isotope Labeling of Amino acids in Cell Culture)-labeled quantitative mass spectrometry proteomics approach, we assessed the effects of erlotinib or cabozantinib resistance on the phosphoproteome, proteome, and kinome. Using this integrated proteomics approach, we identified several potential kinase mediators of cabozantinib resistance and confirmed the contribution of AKT1 to erlotinib resistance in TNBC-resistant cell lines.
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Affiliation(s)
- Cory Lefebvre
- London Regional Cancer Program, London Health Sciences Centre, London, ON N6A 5W9, Canada; (C.L.); (S.P.); (V.B.)
- Department of Anatomy & Cell Biology, Western University, London, ON N6A 3K7, Canada
| | - Sierra Pellizzari
- London Regional Cancer Program, London Health Sciences Centre, London, ON N6A 5W9, Canada; (C.L.); (S.P.); (V.B.)
- Department of Anatomy & Cell Biology, Western University, London, ON N6A 3K7, Canada
| | - Vasudeva Bhat
- London Regional Cancer Program, London Health Sciences Centre, London, ON N6A 5W9, Canada; (C.L.); (S.P.); (V.B.)
- Department of Anatomy & Cell Biology, Western University, London, ON N6A 3K7, Canada
| | - Kristina Jurcic
- Department of Biochemistry, Western University, London, ON N6A 3K7, Canada; (K.J.); (D.W.L.)
| | - David W. Litchfield
- Department of Biochemistry, Western University, London, ON N6A 3K7, Canada; (K.J.); (D.W.L.)
- Department of Oncology, Western University, London, ON N6A 3K7, Canada
| | - Alison L. Allan
- London Regional Cancer Program, London Health Sciences Centre, London, ON N6A 5W9, Canada; (C.L.); (S.P.); (V.B.)
- Department of Anatomy & Cell Biology, Western University, London, ON N6A 3K7, Canada
- Department of Oncology, Western University, London, ON N6A 3K7, Canada
- Lawson Health Research Institute, London, ON N6A 5W9, Canada
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Lim SM, Fujino T, Kim C, Lee G, Lee YH, Kim DW, Ahn JS, Mitsudomi T, Jin T, Lee SY. BBT-176, a Novel Fourth-Generation Tyrosine Kinase Inhibitor for Osimertinib-Resistant EGFR Mutations in Non-Small Cell Lung Cancer. Clin Cancer Res 2023; 29:3004-3016. [PMID: 37249619 PMCID: PMC10425724 DOI: 10.1158/1078-0432.ccr-22-3901] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 03/14/2023] [Accepted: 05/26/2023] [Indexed: 05/31/2023]
Abstract
PURPOSE Resistance to third-generation EGFR inhibitors including osimertinib arises in part from the C797S mutation in EGFR. Currently, no targeted treatment option is available for these patients. We have developed a new EGFR tyrosine kinase inhibitor (TKI), BBT-176, targeting the C797S mutation. PATIENTS AND METHODS Recombinant EGFR proteins and Ba/F3 cell lines, patient-derived cells, and patient-derived xenografts expressing mutant EGFRs were used to test the inhibitory potency and the anticancer efficacy of BBT-176 both in vitro and in vivo. Patient case data are also available from an ongoing phase I clinical trial (NCT04820023). RESULTS The half maximal inhibitory concentration (IC50) of BBT-176 against EGFR 19Del/C797S, EGFR 19Del/T790M/C797S, and EGFR L858R/C797S proteins were measured at 4.36, 1.79, and 5.35 nmol/L, respectively (vs. 304.39, 124.82, and 573.72 nmol/L, for osimertinib). IC50 values of BBT-176 against Ba/F3 cells expressing EGFR 19Del/C797S, EGFR 19Del/T790M/C797S, EGFR L858R/C797S, and EGFR L858R/T790M/C797S were 42, 49, 183, and 202 nmol/L, respectively (vs. 869, 1,134, 2,799, and 2,685 nmol/L for osimertinib). N-ethyl-N-nitrosourea mutagenesis suggested that BBT-176 treatment does not introduce any secondary mutations in the EGFR gene but increases EGFR expression levels. Combined with the EGFR antibody cetuximab, BBT-176 effectively suppressed the growth of BBT-176-resistant clones. BBT-176 strongly inhibited the tumor growth, and in some conditions induced tumor regression in mouse models. In the clinical trial, two patients harboring EGFR 19Del/T790M/C797S in blood showed tumor shrinkage and radiologic improvements. CONCLUSIONS BBT-176 is a fourth-generation EGFR inhibitor showing promising preclinical activity against NSCLC resistant to current EGFR TKI, with early clinical efficacy and safety.
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Affiliation(s)
- Sun Min Lim
- Department of Internal Medicine, Yonsei University, Seoul, Republic of Korea (South)
| | - Toshio Fujino
- Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Chulwon Kim
- Bridge Biotherapeutics Inc., Seongnam-si, Republic of Korea (South)
| | - Gwanghee Lee
- Boostimmune, Inc., Seoul, Republic of Korea (South)
| | - Yong-Hee Lee
- Bridge Biotherapeutics Inc., Newton, Massachusetts
| | - Dong-Wan Kim
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Republic of Korea (South)
| | - Jin Seok Ahn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University, Seoul, Republic of Korea (South)
| | - Tetsuya Mitsudomi
- Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Taiguang Jin
- Bridge Biotherapeutics Inc., Newton, Massachusetts
| | - Sang-Yoon Lee
- Bridge Biotherapeutics Inc., Seongnam-si, Republic of Korea (South)
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Minami S, Shoshihara N. Long-Term Responders to Erlotinib for Pulmonary Adenocarcinoma With Wild-Type Epidermal Growth Factor Receptor: Two Case Reports and a Single-Institutional Retrospective Study. World J Oncol 2023; 14:101-107. [PMID: 36895989 PMCID: PMC9990727 DOI: 10.14740/wjon1554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Accepted: 01/26/2023] [Indexed: 03/01/2023] Open
Abstract
Erlotinib is an oral and reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and is now used exclusively to non-small cell lung carcinoma (NSCLC) harboring mutated EGFR. However, there was historically a transient period when erlotinib was widely used regardless of EGFR mutation status. We report two cases with adenocarcinoma and wild-type EGFR status, which responded to erlotinib for unusual long time. We also retrospectively analyzed patients with adenocarcinoma and wild-type EGFR mutation status who had received erlotinib-containing regimen in our hospital. A 60-year-old woman received the second-line and tri-weekly regimen of pemetrexed (500 mg/m2 on day 1) and intermittent erlotinib (150 mg on days 2 - 16). Pemetexed was discontinued 18 months after the initiation of this regimen, but erlotinib was continued for more than 11 years. This chemotherapy successfully reduced her brain metastasis and prevented recurrence. A 58-year-old man received erlotinib monotherapy as the third-line regimen, by which multiple brain metastases disappeared. Although we tried stopping erlotinib 9 years after the initiation of erlotinib, a solitary metastasis appeared in the brain 3 months after the discontinuation of erlotinib. Between December 2007 and October 2015, 39 patients with wild-type EGFR status initiated erlotinib-containing regimens at our hospital. The response rate, progression-free survival and overall survival were 17.9% (95% confidence interval (CI): 7.5-33.5%), 2.7 months (95% CI: 1.8 - 5.0 months) and 10.3 months (95% CI: 5.0 - 15.7 months), respectively. We reported two long-term responders and survivors to erlotinib for more than 9 years, which was much longer than patients with adenocarcinoma and wild-type EGFR mutation status who had received erlotinib-containing regimen in our hospital.
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Affiliation(s)
- Seigo Minami
- Department of Respiratory Medicine, Osaka Police Hospital, Osaka, Japan
| | - Nao Shoshihara
- Department of Respiratory Medicine, Osaka Police Hospital, Osaka, Japan
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28
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Sex differences in drug effects and/or toxicity in oncology. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2023; 4:100152. [PMID: 36714036 PMCID: PMC9881040 DOI: 10.1016/j.crphar.2022.100152] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 12/19/2022] [Accepted: 12/22/2022] [Indexed: 01/19/2023] Open
Abstract
The prevalence, incidence, and severity of a wide variety of diseases and ailments are significantly influenced by the significant disparities that occur between the sexes. The way that men and women react to pharmacological treatment also varies. Therefore, it is crucial to comprehend these reactions in order to conduct risk assessment correctly and to develop safe and efficient therapies. Even from that limited vantage point, the manner and timing of our drug usage might have unintended and unanticipated consequences. There are sex-specific differences in the incidence and mortality of certain malignancies. One of the most important discoveries in cancer epidemiology is the gender inequalities. Cancer incidence differences between the sexes are thought to be regulated at the genetic and molecular levels and by sex hormones like oestrogen. Differences based on sex and gender are among the least investigated factors impacting cancer susceptibility, progression, survival, and therapy response despite their established importance in clinical care. The molecular mechanisms underlying sex differences in particular are poorly known, hence the majority of precision medicine approaches employ mutational or other genetic data to assign therapy without taking into account how the patient's sex may affect therapeutic efficacy. In patients receiving chemotherapy, there are definite gender-dependent disparities in response rates and the likelihood of side effects. This review explores the influence of sex as a biological variable in drug effects or toxicity in oncology.
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Signaling pathways and targeted therapies in lung squamous cell carcinoma: mechanisms and clinical trials. Signal Transduct Target Ther 2022; 7:353. [PMID: 36198685 PMCID: PMC9535022 DOI: 10.1038/s41392-022-01200-x] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 09/03/2022] [Accepted: 09/18/2022] [Indexed: 11/08/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related death across the world. Unlike lung adenocarcinoma, patients with lung squamous cell carcinoma (LSCC) have not benefitted from targeted therapies. Although immunotherapy has significantly improved cancer patients' outcomes, the relatively low response rate and severe adverse events hinder the clinical application of this promising treatment in LSCC. Therefore, it is of vital importance to have a better understanding of the mechanisms underlying the pathogenesis of LSCC as well as the inner connection among different signaling pathways, which will surely provide opportunities for more effective therapeutic interventions for LSCC. In this review, new insights were given about classical signaling pathways which have been proved in other cancer types but not in LSCC, including PI3K signaling pathway, VEGF/VEGFR signaling, and CDK4/6 pathway. Other signaling pathways which may have therapeutic potentials in LSCC were also discussed, including the FGFR1 pathway, EGFR pathway, and KEAP1/NRF2 pathway. Next, chromosome 3q, which harbors two key squamous differentiation markers SOX2 and TP63 is discussed as well as its related potential therapeutic targets. We also provided some progress of LSCC in epigenetic therapies and immune checkpoints blockade (ICB) therapies. Subsequently, we outlined some combination strategies of ICB therapies and other targeted therapies. Finally, prospects and challenges were given related to the exploration and application of novel therapeutic strategies for LSCC.
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30
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Placebo effect in the treatment of non-small cell lung cancer: a meta-analysis. JOURNAL OF BIO-X RESEARCH 2022. [DOI: 10.1097/jbr.0000000000000123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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31
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Oxidized tea polyphenol (OTP-3) targets EGFR synergistic nimotuzumab at inhibition of non-small cell lung tumor growth. Bioorg Chem 2022; 128:106084. [DOI: 10.1016/j.bioorg.2022.106084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/30/2022] [Accepted: 08/03/2022] [Indexed: 11/21/2022]
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Barlesi F, Tomasini P, Karimi M, Michiels S, Raimbourg J, Daniel C, Janicot H, Madroszyk A, Audigier-Valette C, Quoix E, Mazieres J, Moro-Sibilot D, Dansin E, Molinier O, Morel H, Pichon E, Cortot A, Otto J, Chomy FO, Souquet PJ, Cloarec N, Giroux Leprieur E, Bieche I, Lacroix L, Boyault S, Attignon V, Soubeyran I, Morel A, Tran-Dien A, Jacquet A, Dall'Olio FG, Jimenez M, Soria JC, Besse B. Comprehensive genome profiling in patients with metastatic non-small cell lung cancer: the precision medicine phase 2 randomized SAFIR02-Lung trial. Clin Cancer Res 2022; 28:4018-4026. [PMID: 35802649 DOI: 10.1158/1078-0432.ccr-22-0371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 04/20/2022] [Accepted: 07/06/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non-small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown. EXPERIMENTAL DESIGN SAFIR02-Lung was an open-label, randomized, phase 2 trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared to standard-of-care as a maintenance strategy in advanced EGFR, ALK wild-type (wt) NSCLC patients without progression after first line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS). RESULTS Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months (95% CI 1.6-2.9) with TT vs. 2.7 months (1.6-4.1) with standard-of-care (HR 0.97, 0.7-1.36; p=0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3-4.4) with durvalumab versus 3.0 months (2.0-5.1) with standard-of-care (HR=0.86; 0.62-1.20; p=0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 Tumor Proportion Score (TPS) ≥ 1%, (n=29, HR=0.29; 0.11-0.75) as compared to PD-L1 <1% (n=31, HR=0.71, 0.31-1.60, interaction p= 0.036). CONCLUSIONS Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in the current study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients.
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Affiliation(s)
- Fabrice Barlesi
- Aix Marseille University, CNRS, INSERM, CRCM, APHM, Marseille, France
| | - Pascale Tomasini
- Aix Marseille University, CNRS, INSERM, CRCM, APHM, Marseille, France
| | | | | | | | | | - Henri Janicot
- CHU - Hopital Gabriel Montpied, Clermont-Ferrand, France
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Alain Morel
- Institut de Cancérologie de l'Ouest, Angers, France
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YANG X, MEI T, YU M, GONG Y. Symptomatic Radiation Pneumonitis in NSCLC Patients Receiving EGFR-TKIs and Concurrent Once-daily Thoracic Radiotherapy: Predicting the Value of Clinical and Dose-volume Histogram Parameters. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2022; 25:409-419. [PMID: 35747920 PMCID: PMC9244499 DOI: 10.3779/j.issn.1009-3419.2022.102.17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND The incidence of symptomatic radiation pneumonitis (RP) and its relationship with dose-volume histogram (DVH) parameters in non-small cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and concurrent once-daily thoracic radiotherapy (TRT) remain unclear. We aim to analyze the values of clinical factors and dose-volume histogram (DVH) parameters to predict the risk for symptomatic RP in these patients. METHODS Between 2011 and 2019, we retrospectively analyzed and identified 85 patients who had received EGFR-TKIs and once-daily TRT simultaneously (EGFR-TKIs group) and 129 patients who had received concurrent chemoradiotherapy (CCRT group). The symptomatic RP was recorded according to the Common Terminology Criteria for Adverse Event (CTCAE) criteria (grade 2 or above). Statistical analyses were performed using SPSS 26.0. RESULTS In total, the incidences of symptomatic (grade≥2) and severe RP (grade≥3) were 43.5% (37/85) and 16.5% (14/85) in EGFR-TKIs group vs 27.1% (35/129) and 10.1% (13/129) in CCRT group respectively. After 1:1 ratio between EGFR-TKIs group and CCRT group was matched by propensity score matching, chi-square test suggested that the incidence of symptomatic RP in the MATCHED EGFR-TKIs group was higher than that in the matched CCRT group (χ2=4.469, P=0.035). In EGFR-TKIs group, univariate and multivariate analyses indicated that the percentage of ipsilateral lung volume receiving ≥30 Gy (ilV30) [odds ratio (OR): 1.163, 95%CI: 1.036-1.306, P=0.011] and the percentage of total lung volume receiving ≥20 Gy (tlV20) (OR: 1.171, 95%CI: 1.031-1.330, P=0.015), with chronic obstructive pulmonary disease (COPD) or not (OR: 0.158, 95%CI: 0.041-0.600, P=0.007), were independent predictors of symptomatic RP. Compared to patients with lower ilV30/tlV20 values (ilV30 and tlV20<cut-off point values) and without COPD, patients with higher ilV30/tlV20 values (ilV30 and tlV20>cut-off point values) and COPD had a significantly higher risk for developing symptomatic RP, with a hazard ratio (HR) of 1.350 (95%CI: 1.190-1.531, P<0.001). CONCLUSIONS Patients receiving both EGFR-TKIs and once-daily TRT were more likely to develop symptomatic RP than patients receiving concurrent chemoradiotherapy. The ilV30, tlV20, and comorbidity of COPD may predict the risk of symptomatic RP among NSCLC patients receiving EGFR-TKIs and conventionally fractionated TRT concurrently.
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Affiliation(s)
- Xuexi YANG
| | - Ting MEI
| | - Min YU
| | - Youling GONG
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34
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Chen L, You Q, Liu M, Li S, Wu Z, Hu J, Ma Y, Xia L, Zhou Y, Xu N, Zhang S. Remodeling of dermal adipose tissue alleviates cutaneous toxicity induced by anti-EGFR therapy. eLife 2022; 11:72443. [PMID: 35324426 PMCID: PMC8947768 DOI: 10.7554/elife.72443] [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: 07/23/2021] [Accepted: 03/14/2022] [Indexed: 12/12/2022] Open
Abstract
Anti-epidermal growth factor receptor (EGFR) therapy–associated cutaneous toxicity is a syndrome characterized by papulopustular rash, local inflammation, folliculitis, and microbial infection, resulting in a decrease in quality of life and dose interruption. However, no effective clinical intervention is available for this adverse effect. Here, we report the atrophy of dermal white adipose tissue (dWAT), a highly plastic adipose tissue with various skin-specific functions, correlates with rash occurrence and exacerbation in a murine model of EGFR inhibitor-induced rash. The reduction in dWAT is due to the inhibition of adipogenic differentiation by defects in peroxisome proliferator-activated receptor γ (PPARγ) signaling, and increased lipolysis by the induced expression of the lipolytic cytokine IL6. The activation of PPARγ by rosiglitazone maintains adipogenic differentiation and represses the transcription of IL6, eventually improving skin functions and ameliorating the severity of rash without altering the antitumor effects. Thus, activation of PPARγ represents a promising approach to ameliorate cutaneous toxicity in patients with cancer who receive anti-EGFR therapy.
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Affiliation(s)
- Leying Chen
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Qing You
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Min Liu
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Shuaihu Li
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Zhaoyu Wu
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Jiajun Hu
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Yurui Ma
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Liangyong Xia
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Zhou
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Nan Xu
- Department of Dermatology, Shanghai East Hospital, Tongji University, Shanghai, China
| | - Shiyi Zhang
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
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Maharati A, Zanguei AS, Khalili-Tanha G, Moghbeli M. MicroRNAs as the critical regulators of tyrosine kinase inhibitors resistance in lung tumor cells. Cell Commun Signal 2022; 20:27. [PMID: 35264191 PMCID: PMC8905758 DOI: 10.1186/s12964-022-00840-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/05/2022] [Indexed: 12/12/2022] Open
Abstract
Lung cancer is the second most common and the leading cause of cancer related deaths globally. Tyrosine Kinase Inhibitors (TKIs) are among the common therapeutic strategies in lung cancer patients, however the treatment process fails in a wide range of patients due to TKIs resistance. Given that the use of anti-cancer drugs can always have side effects on normal tissues, predicting the TKI responses can provide an efficient therapeutic strategy. Therefore, it is required to clarify the molecular mechanisms of TKIs resistance in lung cancer patients. MicroRNAs (miRNAs) are involved in regulation of various pathophysiological cellular processes. In the present review, we discussed the miRNAs that have been associated with TKIs responses in lung cancer. MiRNAs mainly exert their role on TKIs response through regulation of Tyrosine Kinase Receptors (TKRs) and down-stream signaling pathways. This review paves the way for introducing a panel of miRNAs for the prediction of TKIs responses in lung cancer patients.
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