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

被引：200
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：
071010 ; 081704 ;
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
收藏
页码：857 / +
页数：27
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