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

Publication ,  Journal Article
Burgess, MR; Hwang, E; Mroue, R; Bielski, CM; Wandler, AM; Huang, BJ; Firestone, AJ; Young, A; Lacap, JA; Crocker, L; Asthana, S; Davis, EM ...
Published in: Cell
February 23, 2017

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.

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Published In

Cell

DOI

EISSN

1097-4172

Publication Date

February 23, 2017

Volume

168

Issue

5

Start / End Page

817 / 829.e15

Location

United States

Related Subject Headings

  • Retroviridae
  • Proto-Oncogene Proteins p21(ras)
  • Mutation
  • Mice
  • MAP Kinase Signaling System
  • Leukemia, Myeloid, Acute
  • Humans
  • Drug Resistance, Neoplasm
  • Diphenylamine
  • Developmental Biology
 

Citation

APA
Chicago
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MLA
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Burgess, M. R., Hwang, E., Mroue, R., Bielski, C. M., Wandler, A. M., Huang, B. J., … Shannon, K. (2017). KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer. Cell, 168(5), 817-829.e15. https://doi.org/10.1016/j.cell.2017.01.020
Burgess, Michael R., Eugene Hwang, Rana Mroue, Craig M. Bielski, Anica M. Wandler, Benjamin J. Huang, Ari J. Firestone, et al. “KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer.Cell 168, no. 5 (February 23, 2017): 817-829.e15. https://doi.org/10.1016/j.cell.2017.01.020.
Burgess MR, Hwang E, Mroue R, Bielski CM, Wandler AM, Huang BJ, et al. KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer. Cell. 2017 Feb 23;168(5):817-829.e15.
Burgess, Michael R., et al. “KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer.Cell, vol. 168, no. 5, Feb. 2017, pp. 817-829.e15. Pubmed, doi:10.1016/j.cell.2017.01.020.
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. KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer. Cell. 2017 Feb 23;168(5):817-829.e15.
Journal cover image

Published In

Cell

DOI

EISSN

1097-4172

Publication Date

February 23, 2017

Volume

168

Issue

5

Start / End Page

817 / 829.e15

Location

United States

Related Subject Headings

  • Retroviridae
  • Proto-Oncogene Proteins p21(ras)
  • Mutation
  • Mice
  • MAP Kinase Signaling System
  • Leukemia, Myeloid, Acute
  • Humans
  • Drug Resistance, Neoplasm
  • Diphenylamine
  • Developmental Biology