Disruption of CRAF-Mediated MEK Activation Is Required for Effective MEK Inhibition in KRAS Mutant Tumors

作者：Lito Piro; Saborowski Anna; Yue Jingyin; Solomon Martha; Joseph Eric; Gadal Sunyana; Saborowski Michael; Kastenhuber Edward; Fellmann Christof; Ohara Kazuhiro; Morikami Kenji; Miura Takaaki; Lukacs Christine; Ishii Nobuya; Lowe Scott^*; Rosen Neal

来源：Cancer Cell, 2014, 25(5): 697-710.

DOI：10.1016/j.ccr.2014.03.011

MEK inhibitors are clinically active in BRAF(V600E) melanomas but only marginally so in KRAS mutant tumors. Here, we found that MEK inhibitors suppress ERK signaling more potently in BRAF(V600E), than in KRAS mutant tumors. To understand this, we performed an RNAi screen in a KRAS mutant model and found that CRAF knockdown enhanced MEK inhibition. MEK activated by CRAF was less susceptible to MEK inhibitors than when activated by BRAF(V600E). MEK inhibitors induced RAF-MEK complexes in KRAS mutant models, and disrupting such complexes enhanced inhibition of CRAF-dependent ERK signaling. Newer MEK inhibitors target MEK catalytic activity and also impair its reactivation by CRAF, either by disrupting RAF-MEK complexes or by interacting with Ser 222 to prevent MEK phosphorylation by RAF.

• 出版日期2014-5-12