Format

Send to

Choose Destination
Cancer Res. 2017 Aug 15;77(16):4498-4505. doi: 10.1158/0008-5472.CAN-16-1944. Epub 2017 May 18.

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

Author information

1
Division of Hematology and Oncology, Department of Medicine and Helen Diller Family Comprehensive Cancer Center University of California, San Francisco, California.
2
Thoracic Cancer Unit, Davidoff Cancer Center and Tel Aviv University, Petach Tiqwa, Israel.
3
Dana-Farber Cancer Institute, Boston, Massachusetts.
4
Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California.
5
Department of Pathology, University of California, San Francisco, San Francisco, California.
6
Department of Biomedical Engineering, University of California, Santa Cruz, Santa Cruz, California.
7
Division of Hematology and Oncology, Department of Medicine and Helen Diller Family Comprehensive Cancer Center University of California, San Francisco, California. collissonlab@gmail.com.

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. Cancer Res; 77(16); 4498-505. ©2017 AACR.

PMID:
28522754
PMCID:
PMC6004099
DOI:
10.1158/0008-5472.CAN-16-1944
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center