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

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

  • Sci Transl Med. 2021 Sep;13(609):eabb3738. doi: 10.1126/scitranslmed.abb3738.
Pınar Özden Eser 1 2 3 4,  Raymond M Paranal 1 2,  Jieun Son 1 2 3,  Elena Ivanova 5,  Yanan Kuang 5,  Heidi M Haikala 1 2 3,  Ciric To 1 2 3,  Jeffrey J Okoro 1 2,  Kshiti H Dholakia 1 2,  Jihyun Choi 1 2,  Yoonji Eum 1 2,  Atsuko Ogino 1 2 3,  Pavlos Missios 6,  Dalia Ercan 1 2,  Man Xu 5,  Michael J Poitras 7,  Stephen Wang 5,  Kenneth Ngo 5,  Michael Dills 5,  Masahiko Yanagita 2 5,  Timothy Lopez 1 2,  Mika Lin 1 2,  Jeanelle Tsai 1 2,  Nicolas Floch 8,  Emily S Chambers 1,  Jennifer Heng 1,  Rana Anjum 9,  Alison D Santucci 1 2,  Kesi Michael 2,  Alwin G Schuller 9,  Darren Cross 10,  Paul D Smith 8,  Geoffrey R Oxnard 1 3,  David A Barbie 1 2 3 5,  Lynette M Sholl 11,  Magda Bahcall 1 2 3,  Sangeetha Palakurthi 5,  Prafulla C Gokhale 5 7,  Cloud P Paweletz 5,  George Q Daley 4 6 12,  Pasi A Jänne 1 2 3 5
Affiliations

Affiliations

  • 1 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 3 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
  • 4 Harvard Medical School, Boston, MA 02115, USA.
  • 5 Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 6 Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA.
  • 7 Experimental Therapeutics Core, Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 8 Oncology R&D, Bioscience, AstraZeneca, CRUK Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK.
  • 9 Bioscience, Oncology R&D, AstraZeneca, 25 Gatehouse Park, Waltham, MA 02451, USA.
  • 10 Global Medical Affairs, Oncology Business Unit, AstraZeneca, 136 Hills Road, Cambridge CB2 8PA, UK.
  • 11 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
  • 12 Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
PMID: 34516823 DOI: 10.1126/scitranslmed.abb3738
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.

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