BRAF Mutant Gastrointestinal Stromal Tumor: First report of regression with BRAF inhibitor dabrafenib (GSK2118436) and whole exomic sequencing for analysis of acquired resistance
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G.S. Falchook1, J.C. Trent2, M.C. Heinrich3, C. Beadling3, J. Patterson3, C.C. Bastida1, S.C. Blackman4, R. Kurzrock5
1 Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
2 Sarcoma Medical Oncology Program, University of Miami, Sylvester Comprehensive Cancer Center, Miami, Florida
3 Portland VA Medical Center and Oregon Health & Science University (OHSU) Knight Cancer Institute, Division of Hematology & Oncology, Portland, Oregon
4 GlaxoSmithKline, Collegeville, PA
5 Moores Cancer Center, Department of Medicine, Hematology-Oncology Division, The University of California, San Diego, La Jolla, CA
Gerald Falchook, email:
Keywords: Gastrointestinal stromal tumor, Dabrafenib, GSK2118436, BRAF mutation, BRAF inhibition, V600E
Received: February 8, 2013 Accepted: February 24, 2013 Published: February 25, 2013
Activating oncogenic mutations of BRAF have been described in patients with gastrointestinal stromal tumor (GIST), but treatment of GIST with BRAF inhibitors and mechanisms of mediating the emergence of resistance in GIST have not been reported. Dabrafenib is a potent ATP-competitive inhibitor of BRAF kinase and is highly selective for mutant BRAF in kinase panel screening, cell lines, and xenografts. We report prolonged antitumor activity in the first patient with V600E BRAF-mutated GIST who was treated with a BRAF inhibitor. Whole exome sequencing performed in tumor tissue obtained at the time of progressive disease demonstrated a somatic gain-of-function PIK3CA mutation (H1047R) as well as a CDKN2A aberration, which may have contributed to eventual resistance to treatment.
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