MET exon 14 mutation encodes an actionable therapeutic target in lung adenocarcinoma

Xinyuan Lu, Nir Peled, John Greer, Wei Wu, Peter Choi, Alice H. Berger, Sergio Wong, Kuang-Yu Jen, Youngho Seo, Byron Hann, Angela Brooks, Matthew Meyerson, Eric A. Collisson

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Targeting somatically activated oncogenes has revolutionized the treatment of non–small cell lung cancer (NSCLC). Mutations in the gene mesenchymal–epithelial transition (MET) near the exon 14 splice sites are recurrent in lung adenocarcinoma and cause exon skipping (METΔ14). Here, we analyzed 4,422 samples from 12 different malignancies to estimate the rate of said exon skipping. METΔ14 mutation and transcript were most common in lung adenocarcinoma. Endogenously expressed levels of METΔ14 transformed human epithelial lung cells in a hepatocyte growth factor–dependent manner. In addition, overexpression of the orthologous mouse allele induced lung adenocarcinoma in a novel, immunocompetent mouse model. Met inhibition showed clinical benefit in this model. In addition, we observed a clinical response to crizotinib in a patient with METΔ14-driven NSCLC, only to observe new missense mutations in the MET activation loop, critical for binding to crizotinib, upon clinical progression. These findings support genomically selected clinical trials directed toward METΔ14 in a fraction of NSCLC patients, confirm second-site mutations for further therapeutic targeting prior to and beyond acquired resistance, and provide an in vivo system for the study of METΔ14 in an immunocompetent host.

Original languageEnglish (US)
Pages (from-to)4498-4505
Number of pages8
JournalCancer Research
Volume77
Issue number16
DOIs
StatePublished - Aug 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Lu, X., Peled, N., Greer, J., Wu, W., Choi, P., Berger, A. H., Wong, S., Jen, K-Y., Seo, Y., Hann, B., Brooks, A., Meyerson, M., & Collisson, E. A. (2017). MET exon 14 mutation encodes an actionable therapeutic target in lung adenocarcinoma. Cancer Research, 77(16), 4498-4505. https://doi.org/10.1158/0008-5472.CAN-16-1944