Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping.

Abstract

UNLABELLED:

Mutations in the MET exon 14 RNA splice acceptor and donor sites, which lead to exon skipping, deletion of the juxtamembrane domain containing the CBL E3-ubiquitin ligase-binding site, and decreased turnover of the resultant aberrant MET protein, were previously reported to be oncogenic in preclinical models. We now report responses to the MET inhibitors crizotinib and cabozantinib in four patients with stage IV lung adenocarcinomas harboring mutations leading to MET exon 14 skipping, highlighting a new therapeutic strategy for the 4% of lung adenocarcinoma patients whose tumors harbor this previously underappreciated genetic alteration.

SIGNIFICANCE:

Oncogenic mutations in the MET exon 14 splice sites that cause exon 14 skipping occur in 4% of lung adenocarcinomas. We report responses to the MET inhibitors crizotinib and cabozantinib in patients with lung adenocarcinomas harboring MET exon 14 splice site mutations, identifying a new potential therapeutic target in this disease.

• Authors: Paul K Paik, Alexander Drilon, Pang-Dian Fan, Helena Yu, Natasha Rekhtman, Michelle S Ginsberg, Laetitia Borsu, Nikolaus Schultz, Michael F Berger, Charles M Rudin, Marc Ladanyi
• Journal: Cancer discovery (Cancer Discov) Vol. 5 Issue 8 Pg. 842-9 (Aug 2015) ISSN: 2159-8290 [Electronic] United States
• PMID: 25971939 (Publication Type: Journal Article)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• RNA Splice Sites
• Proto-Oncogene Proteins c-met

Topics

• Adenocarcinoma (diagnosis, drug therapy, genetics, mortality)
• Adenocarcinoma of Lung
• Aged
• Aged, 80 and over
• Alternative Splicing
• Antineoplastic Agents (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• DNA Copy Number Variations
• Exons
• Female
• Humans
• Lung Neoplasms (diagnosis, drug therapy, genetics, mortality)
• Male
• Middle Aged
• Mutation
• Neoplasm Grading
• Neoplasm Metastasis
• Neoplasm Staging
• Positron-Emission Tomography
• Protein Kinase Inhibitors (therapeutic use)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors, genetics, metabolism)
• RNA Splice Sites
• Treatment Outcome