C-RAF mutations confer resistance to RAF inhibitors
Menée sur des lignées cellulaires de mélanome, cette étude identifie des mutations du gène C-RAF en association avec une résistance à un traitement par inhibiteur de RAF
Melanomas that contain B-RAFV600E mutations respond transiently to RAF and MEK inhibitors; however, resistance to these agents remains a formidable challenge. Although B- or C-RAF dysregulation represent prominent resistance mechanisms, resistance-associated point mutations in RAF oncoproteins are surprisingly rare. To gain insights herein, we performed random mutagenesis screens to identify B- or C-RAF mutations that confer resistance to RAF inhibitors. Whereas bona fide B-RAFV600E resistance alleles were rarely observed, we identified multiple C-RAF mutations that produced biochemical and pharmacological 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 up-regulation 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.