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

Michael R. Burgess, Eugene Hwang, Rana Mroue, Craig M. Bielski, Anica M. Wandler, Benjamin J. Huang, Ari J. Firestone, Amy Young, Jennifer A. Lacap, Lisa Crocker, Saurabh Asthana, Elizabeth M. Davis, Jin Xu, Keiko Akagi, Michelle M. Le Beau, Qing Li, Benjamin Haley, David Stokoe, Deepak Sampath, Barry S. TaylorMarie Evangelista, Kevin Shannon

Research output: Contribution to journalArticlepeer-review

123 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)817-829.e15
JournalCell
Volume168
Issue number5
DOIs
StatePublished - Feb 23 2017
Externally publishedYes

Keywords

  • AML
  • KRAS
  • MEK inhibition
  • allelic imbalance
  • colorectal cancer
  • drug resistance

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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