<i>MET</i> 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 (<i>MET</i>) near the exon 14 splice sites are recurrent in lung adenocarcinoma and cause exon skipping (<i>MET</i>Δ14). Here, we analyzed 4,422 samples from 12 different malignancies to estimate the rate of said exon skipping. <i>MET</i>Δ14 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 <i>MET</i>Δ14 in a fraction of NSCLC patients, confirm second-site mutations for further therapeutic targeting prior to and beyond acquired resistance, and provide an <i>in vivo</i> system for the study of <i>MET</i>Δ14 in an immunocompetent host. <i>Cancer Res; 77(16); 4498-505. ©2017 AACR</i>.