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

作者：Lu Xinyuan; Peled Nir; Greer John; Wu Wei; Choi Peter; Berger Alice H; Wong Sergio; Jen Kuang Yu; Seo Youngho; Hann Byron; Brooks Angela; Meyerson Matthew; Collisson Eric A^*

来源：Cancer Research, 2017, 77(16): 4498-4505.

DOI：10.1158/0008-5472.CAN-16-1944

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 Delta 14). Here, we analyzed 4,422 samples from 12 different malignancies to estimate the rate of said exon skipping. MET Delta 14 mutation and transcript were most common in lung adenocarcinoma. Endogenously expressed levels of MET Delta 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 Delta 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 Delta 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 Delta 14 in an immunocompetent host.

• 出版日期2017-8-15