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Oncogenic switch and single-agent MET inhibitor sensitivity in a subset of EGFR-mutant lung cancer.


ABSTRACT: 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.

SUBMITTER: Eser PO 

PROVIDER: S-EPMC8627689 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Oncogenic switch and single-agent MET inhibitor sensitivity in a subset of <i>EGFR</i>-mutant lung cancer.

Eser Pınar Özden PÖ   Paranal Raymond M RM   Son Jieun J   Ivanova Elena E   Kuang Yanan Y   Haikala Heidi M HM   To Ciric C   Okoro Jeffrey J JJ   Dholakia Kshiti H KH   Choi Jihyun J   Eum Yoonji Y   Ogino Atsuko A   Missios Pavlos P   Ercan Dalia D   Xu Man M   Poitras Michael J MJ   Wang Stephen S   Ngo Kenneth K   Dills Michael M   Yanagita Masahiko M   Lopez Timothy T   Lin Mika M   Tsai Jeanelle J   Floch Nicolas N   Chambers Emily S ES   Heng Jennifer J   Anjum Rana R   Santucci Alison D AD   Michael Kesi K   Schuller Alwin G AG   Cross Darren D   Smith Paul D PD   Oxnard Geoffrey R GR   Barbie David A DA   Sholl Lynette M LM   Bahcall Magda M   Palakurthi Sangeetha S   Gokhale Prafulla C PC   Paweletz Cloud P CP   Daley George Q GQ   Jänne Pasi A PA  

Science translational medicine 20210901 609


The clinical efficacy of epidermal growth factor receptor (EGFR)–targeted therapy in <i>EGFR</i>-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 (<i>MET</i>) proto-oncogene, which bypasses EGFR to reactivate downstream signaling. Tumors exhibiting concurrent <i>EGFR</i> mutation and <i>MET</i> amplification are historically thought to be codependent on t  ...[more]

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