C-RAF Mutations Confer Resistance to RAF Inhibitors
C-RAF Mutations Confer Resistance to RAF Inhibitors
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DOI：
10.1158/0008-5472.can-12-4089
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发表时间：
2013-08-01
期刊：
影响因子：
11.2
通讯作者：
Garraway, Levi A.
中科院分区：
文献类型：
--
作者：
Antony, Rajee;Emery, Caroline M.;Garraway, Levi A.
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. (C)2013 AACR.
