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C-RAF mutations confer resistance to RAF inhibitors.

Content Provider	Semantic Scholar
Author	Antony, Rajee Emery, Caroline M. Sawyer, Allison M. Garraway, Levi A.
Copyright Year	2013
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.
Starting Page	305
Ending Page	319
Page Count	15
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://cancerres.aacrjournals.org/content/canres/early/2013/06/04/0008-5472.CAN-12-4089.full.pdf
Alternate Webpage(s)	http://cancerres.aacrjournals.org/content/canres/73/15/4840.full.pdf
Alternate Webpage(s)	http://cancerres.aacrjournals.org/content/canres/early/2013/07/24/0008-5472.CAN-12-4089.full.pdf
PubMed reference number	23737487v1
Alternate Webpage(s)	https://doi.org/10.1158/0008-5472.CAN-12-4089
DOI	10.1158/0008-5472.can-12-4089
Journal	Cancer research
Volume Number	73
Issue Number	15
Language	English
Access Restriction	Open
Subject Keyword	14-3-3 Proteins Alleles Deploy Mutation Oncogene Proteins Pharmacology RAF1 wt Allele melanoma
Content Type	Text
Resource Type	Article

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