Format

Send to

Choose Destination
See comment in PubMed Commons below
Cancer Res. 2013 Aug 1;73(15):4840-51. doi: 10.1158/0008-5472.CAN-12-4089. Epub 2013 Jun 4.

C-RAF mutations confer resistance to RAF inhibitors.

Author information

1
Department of Medical Oncology, Center for Cancer Genome Discovery, Dana Farber Cancer Institute, Boston, MA 02115, USA.

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.

PMID:
23737487
PMCID:
PMC3748389
DOI:
10.1158/0008-5472.CAN-12-4089
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center