MET Exon 14 Mutation Encodes an Actionable Therapeutic Target in Lung Adenocarcinoma.

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 (MET?14). Here, we analyzed 4,422 samples from 12 different malignancies to estimate the rate of said exon skipping. MET?14 mutation and transcript were most common in lung adenocarcinoma. Endogenously expressed levels of MET?14 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 MET?14-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 MET?14 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 MET?14 in an immunocompetent host. Cancer Res; 77(16); 4498-505. ©2017 AACR.

SUBMITTER: Lu X 

PROVIDER: S-EPMC6004099 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature