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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
Volume73
Issue15
Pages4840-51
Date Published2013 Aug 01
ISSN1538-7445
KeywordsBlotting, Western, Cell Line, Tumor, Cell Proliferation, Drug Resistance, Neoplasm, Humans, Immunoprecipitation, Melanoma, Mutation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-raf
Abstract

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.

URLhttp://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=23737487
DOI10.1158/0008-5472.CAN-12-4089
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23737487?dopt=Abstract

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