| Literature DB >> 29336889 |
Chiara Ambrogio1, Jens Köhler2, Zhi-Wei Zhou3, Haiyun Wang4, Raymond Paranal2, Jiaqi Li2, Marzia Capelletti2, Cristina Caffarra2, Shuai Li2, Qi Lv4, Sudershan Gondi3, John C Hunter3, Jia Lu3, Roberto Chiarle5, David Santamaría6, Kenneth D Westover7, Pasi A Jänne8.
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.Entities:
Keywords: KRAS oncogene; MAPK pathway; MEK inhibitors; allelic imbalance; dimerization; drug resistance; lung adenocarcinoma; wild-type allele
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Year: 2018 PMID： 29336889 DOI： 10.1016/j.cell.2017.12.020
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582