Journal article
Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents
M Mao, F Tian, JM Mariadason, CC Tsao, R Lemos, F Dayyani, YN Vashisht Gopal, ZQ Jiang, II Wistuba, XM Tang, WG Bornman, G Bollag, GB Mills, G Powis, J Desai, GE Gallick, MA Davies, S Kopetz
Clinical Cancer Research | Published : 2013
Abstract
Purpose: Vemurafenib, a selective inhibitor of BRAFV600, has shown significant activity in BRAFV600 melanoma but not in less than 10% of metastatic BRAFV600 colorectal cancers (CRC), suggesting that studies of the unique hypermethylated phenotype and concurrent oncogenic activation of BRAFmut CRC may provide combinatorial strategies. Experimental Design: We conducted comparative proteomic analysis of BRAF V600E melanoma and CRC cell lines, followed by correlation of phosphoinositide 3-kinase (PI3K) pathway activation and sensitivity to the vemurafenib analogue PLX4720. Pharmacologic inhibitors and siRNA were used in combination with PLX4720 to inhibit PI3K and methyltransferase in cell lines..
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Awarded by National Cancer Institute
Funding Acknowledgements
The study was supported by CA136980 (S. Kopetz), CA172670 (S. Kopetz and G. Powis), and the Cancer Center Support Grant CA16672, including the Translational Chemistry Core.J.M. Mariadason has commercial research support from Roche Pharmaceuticals. G. B. Mills has commercial research grants from AstraZeneca, Celgene, CeMines, Exelixis/Sanofi, GSK, Roche, and Wyeth/Pfizer/Puma; has ownership interest (including patents) in Catena Pharm, PTV Ventures, and Spindle Top Ventures; and is a consultant/advisory board member of AstraZeneca, Catena Pharm, Tau Therapeutics, Critical Outcome Tech, Daiichi Pharm, Targeted Molecular Diagnostics LLC, Foundation Medicine, Han AlBio Korea, Komen Foundation, Novartis, and Symphogen. J. Desai has a commercial research grant from Roche. M. A. Davies has commercial research grants from GlaxoSmithKline, Genentech, Merck, Astrazeneca, and Oncothyreon and is a consultant/advisory board member of Glaxosmithkline, Novartis, and Genentech. S. Kopetz has a commercial research grant from Roche and is a consultant/advisory board member of Roche and GSK. No potential conflicts of interest were disclosed by the other authors.