KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS

被引：220

作者：

Ambrogio, Chiara ^{[1
]}

Kohler, Jens ^{[1
]}

Zhou, Zhi-Wei ^{[2
,3
]}

Wang, Haiyun ^{[4
]}

Paranal, Raymond ^{[1
]}

Li, Jiaqi ^{[1
]}

Capelletti, Marzia ^{[1
]}

Caffarra, Cristina ^{[1
]}

Li, Shuai ^{[1
]}

Lv, Qi ^{[4
]}

Gondi, Sudershan ^{[2
,3
]}

Hunter, John C. ^{[2
,3
]}

Lu, Jia ^{[2
,3
]}

Chiarle, Roberto ^{[5
,6
,7
]}

Santamaria, David ^{[8
]}

Westover, Kenneth D. ^{[2
,3
]}

Janne, Pasi A. ^{[1
,9
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[2] Univ Texas Southwestern Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA

[3] Univ Texas Southwestern Med Ctr Dallas, Dept Radiat Oncol, Dallas, TX 75390 USA

[4] Tongji Univ, Sch Life Sci & Technol, Shanghai 200092, Peoples R China

[5] Boston Childrens Hosp, Dept Pathol, Boston, MA 02115 USA

[6] Harvard Med Sch, Boston, MA 02115 USA

[7] Univ Turin, Dept Mol Biotechnol & Hlth Sci, I-10126 Turin, Italy

[8] Univ Bordeaux, INSERM, U1218, ACT Lab,IECB, F-33600 Pessac, France

[9] Dana Farber Canc Inst, Belfer Ctr Appl Canc Sci, Boston, MA 02215 USA

来源：

CELL | 2018年 / 172卷 / 04期

基金：

中国国家自然科学基金;

关键词：

CELL LUNG-CANCER; RAS FORMS DIMERS; WILD-TYPE RAS; THERAPEUTIC STRATEGY; PROLIFERATION; DOCETAXEL; PROTEINS; SURVIVAL; SITE;

D O I：

10.1016/j.cell.2017.12.020

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

The mechanism by which the wild-type KRAS allele imparts a growth inhibitory effect to oncogenic KRAS in various cancers, including lung adenocarcinoma (LUAD), is poorly understood. Here, using a genetically inducible model of KRAS loss of heterozygosity (LOH), we show that KRAS dimerization mediates wild-type KRAS-dependent fitness of human and murine KRAS mutant LUAD tumor cells and underlies resistance to MEK inhibition. These effects are abrogated when wild-type KRAS is replaced by KRAS(D154Q), a mutant that disrupts dimerization at the alpha 4-alpha 5 KRAS dimer interface without changing other fundamental biochemical properties of KRAS, both in vitro and in vivo. Moreover, dimerization has a critical role in the oncogenic activity of mutant KRAS. Our studies provide mechanistic and biological insights into the role of KRAS dimerization and highlight a role for disruption of dimerization as a therapeutic strategy for KRAS mutant cancers.

引用

页码：857 / +

页数：27

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