Reference Detail

Ref Type Journal Article
PMID (28522754)
Authors Lu X, Peled N, Greer J, Wu W, Choi P, Berger AH, Wong S, Jen KY, Seo Y, Hann B, Brooks A, Meyerson M, Collisson EA
Title MET Exon 14 Mutation Encodes an Actionable Therapeutic Target in Lung Adenocarcinoma.
Journal Cancer research
Vol 77
Issue 16
Date 2017 Aug 15
URL
Abstract Text 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. Cancer Res; 77(16); 4498-505. ©2017 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
D1228N missense gain of function MET D1228N lies within the protein kinase domain of the Met protein (UniProt.org). D1228N results in constitutive Met autophosphorylation and increased substrate phosphorylation, and is transforming in cell culture (PMID: 9826708), and has been associated with acquired resistance to Xalkori (crizotinib) (PMID: 28522754). Y
Y1230H missense gain of function MET Y1230H lies within the protein kinase domain of the Met protein (UniProt.org). Y1230H results in constitutive Met autophosphorylation and increased substrate phosphorylation, and is transforming in cell culture (PMID: 9826708), and has been associated with acquired resistance to Xalkori (crizotinib) (PMID: 28522754). Y
Y1230S missense unknown MET Y1230S lies within the protein kinase domain of the Met protein (UniProt.org). Y1230S has been associated with acquired resistance to Xalkori (crizotinib) (PMID: 28522754), but has not been characterized therefore, its effect on Met protein function is unknown (PubMed, Feb 2019). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MET amp MET del exon14 MET D1228N MET G1163R MET Y1230H MET Y1230S lung adenocarcinoma predicted - resistant Crizotinib Case Reports/Case Series Actionable In a clinical case study, a patient with lung adenocarcinoma harboring MET deletion exon 14 responded to Xalkori (crizotinib), demonstrating a near complete response at 3 months, however, after 9 months progression ensued and a re-biospy identified MET del exon14, MET amplification, MET D1228N, MET Y1230H, MET Y1230S, and MET G1163R (PMID: 28522754). 28522754