title: The race to target MET exon 14 skipping alterations in non-small cell lung cancer: The Why, the How, the Who, the Unknown, and the Inevitable.
abstract: A number of small molecule tyrosine kinase inhibitors (TKIs) have now been approved for the treatment of non-small cell lung cancers (NSCLC), including those targeted against epidermal growth factor receptor, anaplastic lymphoma kinase, and ROS1. Despite a wealth of agents developed to target the receptor tyrosine kinase, MET, clinical outcomes have as yet been disappointing, leading to pessimism about the role of MET in the pathogenesis of NSCLC. However, in recent years, there has been a renewed interest in MET exon 14 alterations as potential drivers of lung cancer. MET exon 14 alterations, which result in increased MET protein levels due to disrupted ubiquitin-mediated degradation, occur at a prevalence of around 3% in adenocarcinomas and around 2% in other lung neoplasms, making them attractive targets for the treatment of lung cancer. At least five MET-targeted TKIs, including crizotinib, cabozantinib, capmatinib, tepotinib, and glesatinib, are being investigated clinically for patients with MET exon 14 altered-NSCLC. A further two compounds have shown activity in preclinical models. In this article, we review the current clinical and preclinical data available for these TKIs, along with a number of other potential therapeutic options, including antibodies and immunotherapy. A number of questions remain unanswered regarding the future of MET TKIs, but unfortunately, the development of resistance to targeted therapies is inevitable. Resistance is expected to arise as a result of receptor tyrosine kinase mutation or from upregulation of MET ligand expression; potential strategies to overcome resistance are proposed.
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Thanyanan
authors.initials: T
authors.lastname: Reungwetwattana
authors.affiliation: Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Long Beach Veterans Administration Hospital, Long Beach, CA 90822, USA; Chao Family Comprehensive Cancer Center, Department of Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange County, CA 92868, USA.
authors.forename: Viola
authors.initials: V
authors.lastname: Zhu
authors.affiliation: Chao Family Comprehensive Cancer Center, Department of Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange County, CA 92868, USA. Electronic address: ignatius.ou@uci.edu.
authors.forename: Sai-Hong Ignatius
authors.initials: SI
authors.lastname: Ou
mesh_terms: D017398:Alternative Splicing; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005091:Exons; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases
keywords: Clinical trial; Companion diagnostics; Lung cancer; MET exon 14 skipping; Targeted therapy; Tyrosine kinase inhibitor