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

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

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.

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

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenocarcinoma of Lung* / drug therapy
  • Adenocarcinoma of Lung* / enzymology
  • Adenocarcinoma of Lung* / genetics
  • Adenocarcinoma of Lung* / pathology
  • Amino Acid Substitution
  • Animals
  • Cell Line, Tumor
  • Enzyme Inhibitors / pharmacology*
  • HEK293 Cells
  • Humans
  • Loss of Heterozygosity
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / enzymology
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / pathology
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • Mice, Knockout
  • Mutation, Missense*
  • Protein Multimerization / drug effects*
  • Protein Multimerization / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*

Substances

  • Enzyme Inhibitors
  • KRAS protein, human
  • MAP Kinase Kinase Kinases
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)