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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Burgess, MR; Hwang, E; Mroue, R; Bielski, CM; Wandler, AM; Huang, BJ; Firestone, AJ; Young, A; Lacap, JA; Crocker, L; Asthana, S; Davis, EM; Xu, J; Akagi, K; Le Beau, MM; Li, Q; Haley, B; Stokoe, D; Sampath, D; Taylor, BS; Evangelista, M; Shannon, K

Published Date

  • February 23, 2017

Published In

Volume / Issue

  • 168 / 5

Start / End Page

  • 817 - 829.e15

PubMed ID

  • 28215705

Pubmed Central ID

  • 28215705

Electronic International Standard Serial Number (EISSN)

  • 1097-4172

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2017.01.020

Language

  • eng

Conference Location

  • United States