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- Title
Oncogenic switch and single-agent MET inhibitor sensitivity in a subset of EGFR-mutant lung cancer.
- Authors
Eser, Pınar Özden; Paranal, Raymond M.; Son, Jieun; Ivanova, Elena; Kuang, Yanan; Haikala, Heidi M.; To, Ciric; Okoro, Jeffrey J.; Dholakia, Kshiti H.; Choi, Jihyun; Eum, Yoonji; Ogino, Atsuko; Missios, Pavlos; Ercan, Dalia; Xu, Man; Poitras, Michael J.; Wang, Stephen; Ngo, Kenneth; Dills, Michael; Yanagita, Masahiko
- Abstract
Not bad by half: Many EGFR-mutant non–small cell lung cancer (NSCLC) tumors develop MET amplification. Thought to rely on both pathways for survival, they are thus treated with combination EGFR and MET inhibitors. Eser et al. show that a subset of such tumors cease to rely on their EGFR mutation and become dependent on MET alone. Mice with MET-amplified but mutant EGFR–reduced patient-derived xenografts responded to MET inhibitor monotherapy, suggesting that this type of NSCLC may be treatable in patients with a single therapeutic agent. The clinical efficacy of epidermal growth factor receptor (EGFR)–targeted therapy in EGFR-mutant non–small cell lung cancer is limited by the development of drug resistance. One mechanism of EGFR inhibitor resistance occurs through amplification of the human growth factor receptor (MET) proto-oncogene, which bypasses EGFR to reactivate downstream signaling. Tumors exhibiting concurrent EGFR mutation and MET amplification are historically thought to be codependent on the activation of both oncogenes. Hence, patients whose tumors harbor both alterations are commonly treated with a combination of EGFR and MET tyrosine kinase inhibitors (TKIs). Here, we identify and characterize six patient-derived models of EGFR-mutant, MET-amplified lung cancer that have switched oncogene dependence to rely exclusively on MET activation for survival. We demonstrate in this MET-driven subset of EGFR TKI-refractory cancers that canonical EGFR downstream signaling was governed by MET, even in the presence of sustained mutant EGFR expression and activation. In these models, combined EGFR and MET inhibition did not result in greater efficacy in vitro or in vivo compared to single-agent MET inhibition. We further identified a reduced EGFR:MET mRNA expression stoichiometry as associated with MET oncogene dependence and single-agent MET TKI sensitivity. Tumors from 10 of 11 EGFR inhibitor–resistant EGFR-mutant, MET-amplified patients also exhibited a reduced EGFR:MET mRNA ratio. Our findings reveal that a subset of EGFR-mutant, MET-amplified lung cancers develop dependence on MET activation alone, suggesting that such patients could be treated with a single-agent MET TKI rather than the current standard-of-care EGFR and MET inhibitor combination regimens.
- Subjects
EPIDERMAL growth factor receptors; LUNG cancer; PROTEIN-tyrosine kinase inhibitors; NON-small-cell lung carcinoma; LUNGS
- Publication
Science Translational Medicine, 2021, Vol 13, Issue 609, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abb3738