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. The tumor-suppressive function of wild-type KRAS depends on its dimerization capacity with mutant KRAS.
Original language | English (US) |
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Pages (from-to) | 857-868.e15 |
Journal | Cell |
Volume | 172 |
Issue number | 4 |
DOIs | |
State | Published - Feb 8 2018 |
Keywords
- KRAS oncogene
- MAPK pathway
- MEK inhibitors
- allelic imbalance
- dimerization
- drug resistance
- lung adenocarcinoma
- wild-type allele
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology