C-RAF mutations confer resistance to RAF inhibitors.

Cancer Res
Authors
Keywords
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.

Year of Publication
2013
Journal
Cancer Res
Volume
73
Issue
15
Pages
4840-51
Date Published
2013 Aug 01
ISSN
1538-7445
URL
DOI
10.1158/0008-5472.CAN-12-4089
PubMed ID
23737487
PubMed Central ID
PMC3748389
Links
Grant list
DP2 OD002750 / OD / NIH HHS / United States
P50 CA093683 / CA / NCI NIH HHS / United States