Activation of MET via Diverse Exon 14 Splicing Alterations Occurs in Multiple Tumor Types and Confers Clinical Sensitivity to MET Inhibitors

Cancer Discovery - Tập 5 Số 8 - Trang 850-859 - 2015
Garrett M. Frampton1, Siraj M. Ali1, Mark R. Rosenzweig1, Juliann Chmielecki1, Xinyuan Lu2, Todd M. Bauer3, Mikhail Akimov4, José A. Bufill5, Carrie B. Lee6, David Jentz7, Rick Hoover7, Sai‐Hong Ignatius Ou8, Ravi Salgia9, Timothy J. Brennan1, Zachary R. Chalmers1, Savina Jaeger10, Alan Huang10, Julia A. Elvin1, Rachel Erlich1, Alex Fichtenholtz1, Kyle Gowen1, Joel Greenbowe1, Adrienne Johnson1, Depinder Khaira1, Caitlin McMahon1, Eric M. Sanford1, Steven Roels1, Jared White1, Joel Greshock10, Robert Schlegel10, Doron Lipson1, Roman Yelensky1, Deborah Morosini1, Jeffrey S. Ross1, Eric A. Collisson2, Malte Peters4, Philip J. Stephens1, Vincent A. Miller1
11Foundation Medicine Inc., Cambridge, Massachusetts.
22Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, California.
33Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, Tennessee.
44Novartis Pharma AG, Basel, Switzerland.
55Michiana Hematology-Oncology, PC, Mishawaka, Indiana.
66University of North Carolina School of Medicine, Clinical Research, Thoracic Oncology Program, Chapel Hill, North Carolina.
77South Bend Medical Foundation, South Bend, Indiana.
88Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, Irvine, California.
99The University of Chicago School of Medicine, Chicago, Illinois.
1010Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.

Tóm tắt

Abstract Focal amplification and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site alterations at MET exon 14 (METex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types are unknown. Here, we report analysis of tumor genomic profiles from 38,028 patients to identify 221 cases with METex14 mutations (0.6%), including 126 distinct sequence variants. METex14 mutations are detected most frequently in lung adenocarcinoma (3%), but also frequently in other lung neoplasms (2.3%), brain glioma (0.4%), and tumors of unknown primary origin (0.4%). Further in vitro studies demonstrate sensitivity to MET inhibitors in cells harboring METex14 alterations. We also report three new patient cases with METex14 alterations in lung or histiocytic sarcoma tumors that showed durable response to two different MET-targeted therapies. The diversity of METex14 mutations indicates that diagnostic testing via comprehensive genomic profiling is necessary for detection in a clinical setting. Significance: Here we report the identification of diverse exon 14 splice site alterations in MET that result in constitutive activity of this receptor and oncogenic transformation in vitro. Patients whose tumors harbored these alterations derived meaningful clinical benefit from MET inhibitors. Collectively, these data support the role of METex14 alterations as drivers of tumorigenesis, and identify a unique subset of patients likely to derive benefit from MET inhibitors. Cancer Discov; 5(8); 850–9. ©2015 AACR. See related commentary by Ma, p. 802. See related article by Paik et al., p. 842. This article is highlighted in the In This Issue feature, p. 783

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Cancer Discovery

Tập 5 Số 8

850-859

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