Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF

被引：1193

作者：

Heidorn, Sonja J. ^{[1
]}

Milagre, Carla ^{[1
]}

Whittaker, Steven ^{[1
]}

Nourry, Arnaud ^{[4
]}

Niculescu-Duvas, Ion ^{[4
]}

Dhomen, Nathalie ^{[1
]}

Hussain, Jahan ^{[2
]}

Reis-Filho, Jorge S. ^{[3
]}

Springer, Caroline J. ^{[4
]}

Pritchard, Catrin ^{[2
]}

Marais, Richard ^{[1
]}

机构：

[1] Inst Canc Res, Signal Transduct Team, Sect Cell & Mol Biol, London SW3 6JB, England

[2] Univ Leicester, Dept Biochem, Leicester LE1 7RH, Leics, England

[3] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England

[4] Inst Canc Res, Gene & Oncogene Targeting Team, Canc Res UK Ctr Canc Therapeut, Sutton SM2 5NG, Surrey, England

来源：

CELL | 2010年 / 140卷 / 02期

基金：

英国惠康基金;

关键词：

B-RAF; K-RAS; ACTIVATION; MELANOMA; INHIBITOR; PATHWAY; HETERODIMERIZATION; MUTATIONS; MECHANISM;

D O I：

10.1016/j.cell.2009.12.040

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We describe a mechanism of tumorigenesis mediated by kinase-dead BRAF in the presence of oncogenic RAS. We show that drugs that selectively inhibit BRAF drive RAS-dependent BRAF binding to CRAF, CRAF activation, and MEK-ERK signaling. This does not occur when oncogenic BRAF is inhibited, demonstrating that BRAF inhibition per se does not drive pathway activation; it only occurs when BRAF is inhibited in the presence of oncogenic RAS. Kinase-dead BRAF mimics the effects of the BRAF-selective drugs and kinase-dead Braf and oncogenic Ras cooperate to induce melanoma in mice. Our data reveal another paradigm of BRAF-mediated signaling that promotes tumor progression. They highlight the importance of understanding pathway signaling in clinical practice and of genotyping tumors prior to administering BRAF-selective drugs, to identify patients who are likely to respond and also to identify patients who may experience adverse effects.

引用

页码：209 / 221

页数：13

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