Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Cancer Cell. 2014 May 12;25(5):697-710. doi: 10.1016/j.ccr.2014.03.011. Epub 2014 Apr 17.
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.
MEK 抑制剂在 BRAF(V600E)黑色素瘤中具有临床活性，但在 KRAS 突变肿瘤中则作用不大。在这里，我们发现 MEK 抑制剂在 BRAF(V600E)中比在 KRAS 突变肿瘤中更能抑制 ERK 信号。为了理解这一点，我们在 KRAS 突变模型中进行了 RNAi 筛选，发现 CRAF 敲低增强了 MEK 抑制。由 CRAF 激活的 MEK 比由 BRAF(V600E)激活的 MEK 对 MEK 抑制剂的敏感性更低。MEK 抑制剂在 KRAS 突变模型中诱导 RAF-MEK 复合物，破坏这种复合物可增强对 CRAF 依赖性 ERK 信号的抑制。新型 MEK 抑制剂靶向 MEK 催化活性，并且还通过破坏 RAF-MEK 复合物或与 Ser 222 相互作用以防止 RAF 对 MEK 的磷酸化，从而损害 CRAF 对 MEK 的再激活。
