Response to MET Inhibitors in Patients with Stage IV Lung Adenocarcinomas Harboring MET Mutations Causing Exon 14 Skipping

Cancer Discovery - Tập 5 Số 8 - Trang 842-849 - 2015
Paul K. Paik1,2, Alexander Drilon1,2, Pang‐Dian Fan3, Helena A. Yu1,2, Natasha Rekhtman3, Michelle S. Ginsberg4, Laetitia Borsu3, Nikolaus Schultz5,6, Michael F. Berger2,3,5, Charles M. Rudin1,2, Marc Ladanyi3,5
11Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
22Weill Cornell Medical College, New York, New York.
33Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
44Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
55Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
66Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.

Tóm tắt

Abstract 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. Cancer Discov; 5(8); 842–9. ©2015 AACR. See related commentary by Ma, p. 802. See related article by Frampton et al., p. 850. This article is highlighted in the In This Issue feature, p. 783

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Cancer Discovery

Tập 5 Số 8

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