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. 2025 Aug;20(8):1035-1049.
doi: 10.1016/j.jtho.2025.03.045. Epub 2025 Apr 2.

Activating Mutations in the MET Kinase Domain Co-Occur With Other Driver Oncogenes and Mediate Resistance to Targeted Therapy in NSCLC

Seshiru Nakazawa  1 , Federica Pecci  2 , Biagio Ricciuti  2 , Felix H Gottlieb  2 , Francesco Facchinetti  2 , Guilherme Harada  3 , Monica F Chen  3 , Matteo Repetto  3 , Flavia Giacomini  4 , Jie Jiang  2 , Marie-Anaïs Locquet  2 , Maisam Makarem  2 , Joao V Alessi  2 , Alessandro Di Federico  2 , Mihaela Aldea  5 , Edoardo Garbo  2 , Malini M Gandhi  2 , Arushi Saini  2 , Danielle Haradon  2 , Magda Bahcall  2 , William W Feng  2 , Jessica K Lee  6 , Alexa B Schrock  6 , Alexander Drilon  3 , Mark M Awad  2 , Pasi A Jänne  7
Affiliations

Activating Mutations in the MET Kinase Domain Co-Occur With Other Driver Oncogenes and Mediate Resistance to Targeted Therapy in NSCLC

Seshiru Nakazawa et al. J Thorac Oncol. 2025 Aug.

Abstract

Introduction: MET tyrosine kinase domain (TKD) mutations have recently been characterized as de novo oncogenic drivers in NSCLC. Nevertheless, whether activating MET TKD mutations can confer resistance to targeted therapy in non-MET, oncogene-driven NSCLCs remains unclear.

Methods: To characterize the genomic features of tumors with MET TKD mutations in oncogene-driven NSCLC, we performed tumor genomic profiling on two different cohorts of patients with NSCLC. Preclinical models of the most frequently observed MET TKD mutations were generated to determine the effect on sensitivity to targeted therapy. Treatment strategies to overcome MET TKD mutation-mediated resistance were further explored.

Results: Genomic profiling of more than 115,000 patients with NSCLC found that activating MET TKD mutations are prevalent in 0.15% of cases, and that about half of them co-occur with another oncogenic driver, with a differential pattern in co-occurring MET TKD mutations according to the oncogenic alteration. A review of eight cases with sequential genomic testing revealed that the MET TKD mutation was acquired after systemic therapy in 88% of cases, with a potential contribution of APOBEC mutagenesis underlying this process. In vitro, MET TKD mutation conferred resistance to targeted therapy in diverse oncogene-driven models, which could be overcome by combinatorial treatment against both the primary oncogene and the MET TKD mutation.

Conclusions: MET TKD mutation can act as an off-target resistance mechanism in diverse oncogene-driven NSCLC. Combination therapy with an effective MET-targeted therapy can potentially overcome MET TKD mutation-mediated resistance.

Keywords: MET tyrosine kinase domain; Mutations; Non–small cell lung cancer; Resistance; Targeted therapy; Tyrosine kinase inhibitor.

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Conflict of interest statement

Disclosure Dr. Ricciuti reports positions on the consulting/advisory boards of Amgen, Regeneron, AstraZeneca, Bristol Mayers Squibb, Bayer, and AbbVie; receiving honoraria from AstraZeneca, Society for Immunotherapy of Cancer, and Targeted Oncology; and speaker fees from AstraZeneca. Dr. Facchinetti reports positions on the advisory board of BeiGene and receiving a speaker’s fee from Roche. Dr. Harada reports receiving honoraria from AstraZeneca, BeiGene, Bristol-Myers Squibb, Daiichi, Eli Lilly, J&J, Merck Sharp Dohme, Novartis, and Takeda. Dr. Chen reports positions on the advisory board of Candel Therapeutics and holding stocks of Doximity, Quest, Figs, and Nordisk. Dr. Alessi reports receiving honoraria as a speaker from MSD, Janssen, AstraZeneca, and Bristol Mayers Squibb; and has participated in advisory boards for Bristol Mayers Squibb, AstraZeneca, Janssen, and Amgen. Dr. Federico reports positions on the scientific advisory board of Hanson-Wade, Novartis, and IQVIA; and receiving honoraria from the Society for Immunotherapy of Cancer. Ms. Lee and Ms. Schrock are employees of Foundation Medicine, a wholly owned subsidiary of Roche, and have stock ownership in Roche. Dr. Drilon reports receiving honoraria from 14ner/Elevation Oncology, Amgen, Abbvie, AnHeart Therapeutics, ArcherDX, AstraZeneca, Beigene, BergenBio, Blueprint Medicines, Bristol Myers Squibb, Boehringer Ingelheim, Chugai Pharmaceutical, EcoR1, EMD Serono, Entos, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta/Genentech/Roche, Janssen, Loxo/Bayer/Lilly, Merus, Monopteros, MonteRosa, Novartis, Nuvalent, Pfizer, Prelude, Regeneron, Repare RX, Springer Healthcare, Takeda/Ariad/Millenium, Treeline Bio, TP Therapeutics, Tyra Biosciences, Verastem, and Zymeworks; holding positions on the advisory boards of Bayer, MonteRosa, Abbvie, EcoR1 Capital, LLC, Amgen, Helsinn, Novartis, Loxo/ Lilly, AnHeart Therapeutics, and Nuvalent; consulting for MonteRosa, Innocare, Boundless Bio, Treeline Bio, Nuvalent, 14ner/Elevation Oncology, Entos, and Prelude; associated research paid to institution from Foundation Medicine, GlaxoSmithKlein, Teva, Taiho, and PharmaMar; holding equity in mBrace and Treeline; holding the copyright for Selpercatinib-Osimertinib (US 18/041,617, pending); receiving royalties from Wolters Kluwer, UpToDate; others (food/beverage) from Merck, Puma, Merus, Boehringer Ingelheim; CME honoraria from Answers in CME, Applied Pharmaceutical Science, Inc, AXIS, Clinical Care Options, Doc Congress, EPG Health, Harborside Nexus, I3 Health, Imedex, Liberum, Medendi, Medscape, Med Learning, MedTalks, MJH Life Sciences, MORE Health, Ology, OncLive, Paradigm, Peerview Institute, PeerVoice, Physicians Education, Projects in Knowledge, Resources, Remedica Ltd, Research to Practice, RV More, Targeted Oncology, TouchIME, and WebMD. Dr. Awad reports grants to institution from Bristol-Myers Squibb, Lilly, Genentech, AstraZeneca, and Amgen; personal consulting fees from Merck, Bristol-Myers Squibb, Genentech, AstraZeneca, Blueprint Medicine, Synthekine, AbbVie, Gritstone, Mirati, Regeneron, AffiniT, EMD Serono, Novartis, Janssen, Coherus, D3Bio, Pfizer, Lilly, Seagen, and Gilead. Dr. Jänne reports holding positions on scientific advice/advisory boards of AbbVie, Accutar Biotech, Allorion Therapeutics, AstraZeneca, Bayer, Biocartis, Blueprint Medicines, Boehringer Ingelheim, Chugai Pharmaceuticals, Daiichi Sankyo, Dizal Pharmaceuticals, Duality Biologics, Eisai Pharmaceuticals, Eli Lilly, Frontier Medicines, Glaxo Smith Kline, Hongyun Biotechnology, Merus, Mirati Therapeutics, Monte Rosa, Novartis, Nuvalent, Pfizer, Roche/Genentech, Scorpion Therapeutics, SFJ Pharmaceuticals, Silicon Therapeutics, Syndax, Takeda Oncology, Transcenta, and Voronoi; sponsorship for research (to Dana Farber Cancer Institute) from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, PUMA, Revolution Medicines, and Takeda Oncology; receiving postmarketing royalties from Dana Farber Cancer Institute owned intellectual property on EGFR mutations licensed to Lab Corp. The remaining authors declare no conflict of interest.

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