Activation Mechanism of Oncogenic Deletion Mutations in BRAF, EGFR, and HER2

被引：172

作者：

Foster, Scott A. ^{[1
]}

Whalen, Daniel M. ^{[2
]}

Oezen, Aysxeguel ^{[3
,4
]}

Wongchenko, Matthew J. ^{[5
]}

Yin, JianPing ^{[2
]}

Yen, Ivana ^{[1
]}

Schaefer, Gabriele ^{[6
]}

Mayfield, John D. ^{[9
]}

Chmielecki, Juliann ^{[9
]}

Stephens, Philip J. ^{[9
]}

Albacker, Lee A. ^{[9
]}

Yan, Yibing ^{[5
]}

Song, Kyung ^{[6
]}

Hatzivassiliou, Georgia ^{[7
]}

Eigenbrot, Charles ^{[2
]}

Yu, Christine ^{[2
]}

Shaw, Andrey S. ^{[1
]}

Manning, Gerard ^{[8
]}

Skelton, Nicholas J. ^{[3
]}

Hymowitz, Sarah G. ^{[2
]}

Malek, Shiva ^{[1
]}

机构：

[1] Genentech Inc, Dept Discovery Oncol, 1 DNA Way, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Prot Chem & Struct Biol, 1 DNA Way, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Discovery Chem, 1 DNA Way, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Early Discovery Biochem, 1 DNA Way, San Francisco, CA 94080 USA

[5] Genentech Inc, Dept Oncol Biomarker Dev, 1 DNA Way, San Francisco, CA 94080 USA

[6] Genentech Inc, Dept Translat Oncol, 1 DNA Way, San Francisco, CA 94080 USA

[7] Genentech Inc, Dept Canc Immunol, 1 DNA Way, San Francisco, CA 94080 USA

[8] Genentech Inc, Dept Bioinformat & Computat Biol, 1 DNA Way, San Francisco, CA 94080 USA

[9] Fdn Med, 150 Second St, Cambridge, MA 02141 USA

来源：

CANCER CELL | 2016年 / 29卷 / 04期

基金：

美国国家卫生研究院;

关键词：

GROWTH-FACTOR RECEPTOR; KINASE DOMAIN; SOMATIC MUTATIONS; CANCER GENOMICS; WILD-TYPE; RAF; RESISTANCE; DIMERIZATION; INHIBITION; MUTANTS;

D O I：

10.1016/j.ccell.2016.02.010

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Activating mutations in protein kinases drive many cancers. While how recurring point mutations affect kinase activity has been described, the effect of in-frame deletions is not well understood. We show that oncogenic deletions within the beta 3-alpha C loop of HER2 and BRAF are analogous to the recurrent EGFR exon 19 deletions. We identify pancreatic carcinomas with BRAF deletions mutually exclusive with KRAS mutations. Crystal structures of BRAF deletions reveal the truncated loop restrains alpha C in an active "in'' conformation, imparting resistance to inhibitors like vemurafenib that bind the alpha C "out'' conformation. Characterization of loop length explains the prevalence of five amino acid deletions in BRAF, EGFR, and HER2 and highlights the importance of this region for kinase activity and inhibitor efficacy.

引用

页码：477 / 493

页数：17

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