KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer

Cell. 2017 Feb 23;168(5):817-829.e15. doi: 10.1016/j.cell.2017.01.020. Epub 2017 Feb 16.


Investigating therapeutic "outliers" that show exceptional responses to anti-cancer treatment can uncover biomarkers of drug sensitivity. We performed preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in KrasG12D "knockin" mice with the MEK inhibitor PD0325901 (PD901). One outlier AML responded and exhibited intrinsic drug resistance at relapse. Loss of wild-type (WT) Kras enhanced the fitness of the dominant clone and rendered it sensitive to MEK inhibition. Similarly, human colorectal cancer cell lines with increased KRAS mutant allele frequency were more sensitive to MAP kinase inhibition, and CRISPR-Cas9-mediated replacement of WT KRAS with a mutant allele sensitized heterozygous mutant HCT116 cells to treatment. In a prospectively characterized cohort of patients with advanced cancer, 642 of 1,168 (55%) with KRAS mutations exhibited allelic imbalance. These studies demonstrate that serial genetic changes at the Kras/KRAS locus are frequent in cancer and modulate competitive fitness and MEK dependency.

Keywords: AML; KRAS; MEK inhibition; allelic imbalance; colorectal cancer; drug resistance.

Publication types

  • Comment

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Benzamides / pharmacology
  • Benzamides / therapeutic use*
  • Cell Line, Tumor
  • Clonal Evolution
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Diphenylamine / analogs & derivatives*
  • Diphenylamine / pharmacology
  • Diphenylamine / therapeutic use
  • Drug Resistance, Neoplasm
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics
  • MAP Kinase Signaling System* / drug effects
  • Mice
  • Mutation
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Retroviridae


  • Antineoplastic Agents
  • Benzamides
  • KRAS protein, human
  • mirdametinib
  • Diphenylamine
  • Proto-Oncogene Proteins p21(ras)