Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition

被引：207

作者：

Wong, Gabrielle S. ^{[1
,2
]}

Zhou, Jin ^{[1
]}

Liu, Jie Bin ^{[1
]}

Wu, Zhong ^{[1
]}

Xu, Xinsen ^{[1
]}

Li, Tianxia ^{[1
]}

Xu, David ^{[3
]}

Schumacher, Steven E. ^{[4
]}

Puschhof, Jens ^{[1
]}

McFarland, James ^{[1
,4
]}

Zou, Charles ^{[1
]}

Dulak, Austin ^{[1
,5
]}

Henderson, Les ^{[3
]}

Xu, Peng ^{[3
]}

O'Day, Emily ^{[3
]}

Rendak, Rachel ^{[3
]}

Liao, Wei-li ^{[6
]}

Cecchi, Fabiola ^{[6
]}

Hembrough, Todd ^{[6
]}

Schwartz, Sarit ^{[6
]}

Szeto, Christopher ^{[6
]}

Rustgi, Anil K. ^{[7
,8
]}

Wong, Kwok-Kin ^{[9
,10
]}

Diehl, J. Alan ^{[11
]}

Jensen, Karin ^{[12
,13
]}

Graziano, Francesco ^{[14
]}

Ruzzo, Annamaria ^{[14
]}

Fereshetian, Shaunt ^{[4
]}

Mertins, Philipp ^{[4
,15
]}

Carr, Steven A. ^{[4
]}

Beroukhim, Rameen ^{[1
,4
,9
,16
,17
]}

Nakamura, Kenichi ^{[18
]}

Oki, Eiji ^{[19
]}

Watanabe, Masayuki ^{[18
,20
]}

Baba, Hideo ^{[18
]}

Imamura, Yu ^{[18
,20
]}

Catenacci, Daniel ^{[3
]}

Bass, Adam J. ^{[1
,4
,9
,16
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[2] Novartis Inst Biomed Res Inc, Cambridge, MA USA

[3] Univ Chicago, Dept Med, Hematol Oncol Sect, Med Ctr & Biol Sci, Chicago, IL 60637 USA

[4] Broad Inst MIT & Harvard, Canc Program, Cambridge, MA 02142 USA

[5] Surface Oncol, Cambridge, MA USA

[6] OncoPlex Diagnost NantOm, Rockville, MD USA

[7] Univ Penn, Dept Med, Div Gastroenterol, Abramson Canc Ctr,Perelman Sch Med, Philadelphia, PA 19104 USA

[8] Univ Penn, Dept Genet, Div Gastroenterol, Abramson Canc Ctr,Perelman Sch Med, Philadelphia, PA 19104 USA

[9] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[10] NYU Langone Hlth, New York, NY USA

[11] Med Univ South Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA

[12] Sanofi Oncol, Cambridge, MA USA

[13] Univ Illinois, Chicago, IL USA

[14] Univ Urbino Carlo Bo, Dept Biomol Sci, Urbino, Italy

[15] Max Delbruck Ctr Mol Med, Berlin, Germany

[16] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA

[17] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[18] Kumamoto Univ, Dept Gastroenterol Surg, Kumamoto, Japan

[19] Kyushu Univ, Grad Sch Med Sci, Dept Surg & Sci, Fukuoka, Japan

[20] Japanese Fdn Canc Res, Canc Inst Hosp, Dept Gastroenterol Surg, Tokyo, Japan

来源：

NATURE MEDICINE | 2018年 / 24卷 / 07期

关键词：

ACQUIRED-RESISTANCE; GENE AMPLIFICATION; COLORECTAL-CANCER; GASTRIC-CANCER; MUTANT LUNG; RAS; ACTIVATION; PHOSPHORYLATION; GROWTH; THERAPY;

D O I：

10.1038/s41591-018-0022-x

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：

The role of KRAS, when activated through canonical mutations, has been well established in cancer(1). Here we explore a secondary means of KRAS activation in cancer: focal high-level amplification of the KRAS gene in the absence of coding mutations. These amplifications occur most commonly in esophageal, gastric and ovarian adenocarcinomas(2-4). KRAS-amplified gastric cancer models show marked overexpression of the KRAS protein and are insensitive to MAPK blockade owing to their capacity to adaptively respond by rapidly increasing KRAS-GTP levels. Here we demonstrate that inhibition of the guanine-exchange factors SOS1 and SOS2 or the protein tyrosine phosphatase SHP2 can attenuate this adaptive process and that targeting these factors, both genetically and pharmacologically, can enhance the sensitivity of KRAS-amplified models to MEK inhibition in both in vitro and in vivo settings. These data demonstrate the relevance of copy-number amplification as a mechanism of KRAS activation, and uncover the therapeutic potential for targeting of these tumors through combined SHP2 and MEK inhibition.

引用

页码：968 / +

页数：13

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