title: C-RAF mutations confer resistance to RAF inhibitors.
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.
authors.affiliation: Department of Medical Oncology, Center for Cancer Genome Discovery, Dana Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Rajee
authors.initials: R
authors.lastname: Antony
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Emery
authors.forename: Allison M
authors.initials: AM
authors.lastname: Sawyer
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D047468:Immunoprecipitation; D008545:Melanoma / Q000235:genetics*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*
chemical_list: D047428:Protein Kinase Inhibitors; D019908:Proto-Oncogene Proteins c-raf