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

被引：243

作者：

Lito, Piro ^{[1
,2
]}

Saborowski, Anna ^{[3
]}

Yue, Jingyin ^{[2
]}

Solomon, Martha ^{[2
]}

Joseph, Eric ^{[2
]}

Gadal, Sunyana ^{[2
]}

Saborowski, Michael ^{[3
]}

Kastenhuber, Edward ^{[3
]}

Fellmann, Christof ^{[7
]}

Ohara, Kazuhiro ^{[5
]}

Morikami, Kenji ^{[5
]}

Miura, Takaaki ^{[5
]}

Lukacs, Christine ^{[6
]}

Ishii, Nobuya ^{[5
]}

Lowe, Scott ^{[3
,4
]}

Rosen, Neal ^{[1
,2
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[2] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA

[4] Howard Hughes Med Inst, New York, NY 10065 USA

[5] Chugai Pharmaceut, Res Div, Kamakura, Kanagawa 2478530, Japan

[6] Hoffmann La Roche Inc, Roche Res Ctr, Nutley, NJ 07110 USA

[7] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

来源：

CANCER CELL | 2014年 / 25卷 / 05期

基金：

美国国家卫生研究院;

关键词：

FEEDBACK INHIBITION; IMPROVED SURVIVAL; C-RAF; BRAF; KINASE; MUTATIONS; IDENTIFICATION; VEMURAFENIB; SENSITIVITY; MECHANISM;

D O I：

10.1016/j.ccr.2014.03.011

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：697 / 710

页数：14

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