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Cancer Res DOI:10.1158/0008-5472.CAN-12-4089

C-RAF mutations confer resistance to RAF inhibitors.

Publication TypeJournal Article
Year of Publication2013
AuthorsAntony, R, Emery, CM, Sawyer, AM, Garraway, LA
JournalCancer Res
Date Published2013 Aug 01
KeywordsBlotting, Western, Cell Line, Tumor, Cell Proliferation, Drug Resistance, Neoplasm, Humans, Immunoprecipitation, Melanoma, Mutation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-raf

Melanomas that contain B-RAF(V600E) mutations respond transiently to RAF and MEK inhibitors; however, resistance to these agents remains a formidable challenge. Although B- or C-RAF dysregulation represents prominent resistance mechanisms, resistance-associated point mutations in RAF oncoproteins are surprisingly rare. To gain insights herein, we conducted random mutagenesis screens to identify B- or C-RAF mutations that confer resistance to RAF inhibitors. Whereas bona fide B-RAF(V600E) resistance alleles were rarely observed, we identified multiple C-RAF mutations that produced biochemical and pharmacologic resistance. Potent C-RAF resistance alleles localized to a 14-3-3 consensus binding site or a separate site within the P loop. These mutations elicited paradoxical upregulation of RAF kinase activity in a dimerization-dependent manner following exposure to RAF inhibitors. Knowledge of resistance-associated C-RAF mutations may enhance biochemical understanding of RAF-dependent signaling, anticipate clinical resistance to novel RAF inhibitors, and guide the design of "next-generation" inhibitors for deployment in RAF- or RAS-driven malignancies.


Alternate JournalCancer Res.
PubMed ID23737487
PubMed Central IDPMC3748389
Grant ListDP2 OD002750 / OD / NIH HHS / United States
P50 CA093683 / CA / NCI NIH HHS / United States