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. 2018 Feb 8;172(4):857-868.e15.
doi: 10.1016/j.cell.2017.12.020. Epub 2018 Jan 11.

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

Chiara Ambrogio  1 , Jens Köhler  2 , Zhi-Wei Zhou  3 , Haiyun Wang  4 , Raymond Paranal  2 , Jiaqi Li  2 , Marzia Capelletti  2 , Cristina Caffarra  2 , Shuai Li  2 , Qi Lv  4 , Sudershan Gondi  3 , John C Hunter  3 , Jia Lu  3 , Roberto Chiarle  5 , David Santamaría  6 , Kenneth D Westover  7 , Pasi A Jänne  8
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KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS

V体育平台登录 - Chiara Ambrogio et al. Cell. .
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"V体育安卓版" Abstract

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 KRASD154Q, a mutant that disrupts dimerization at the α4-α5 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. VSports手机版.

Keywords: KRAS oncogene; MAPK pathway; MEK inhibitors; allelic imbalance; dimerization; drug resistance; lung adenocarcinoma; wild-type allele. V体育安卓版.

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