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

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. [Display omitted] •Wild-type KRAS expression affects cellular fitness in KRAS mutant LUAD•Wild-type KRAS expression impairs response to MEK inhibitors in KRAS mutant LUAD•Wild-type KRAS inhibitory effect is dependent on dimerization with mutant KRAS•Blocking mutant KRAS dimerization impairs oncogenic properties in vivo The tumor-suppressive function of wild-type KRAS depends on its dimerization capacity with mutant KRAS.