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 journalArticle

47 Citations (Scopus)

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

Fingerprint

Allelic Imbalance
Mitogen-Activated Protein Kinase Kinases
Phosphotransferases
Acute Myeloid Leukemia
Clustered Regularly Interspaced Short Palindromic Repeats
HCT116 Cells
Neoplasms
Mutagenesis
Oncology
Insertional Mutagenesis
Biomarkers
Drug Resistance
Gene Frequency
Pharmaceutical Preparations
Colorectal Neoplasms
Therapeutics
Clone Cells
Alleles
Cells
Recurrence

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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

KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer. / Burgess, Michael R.; Hwang, Eugene; Mroue, Rana; Bielski, Craig M.; Wandler, Anica M.; Huang, Benjamin J.; Firestone, Ari J.; Young, Amy; Lacap, Jennifer A.; Crocker, Lisa; Asthana, Saurabh; Davis, Elizabeth M.; Xu, Jin; Akagi, Keiko; Le Beau, Michelle M.; Li, Qing; Haley, Benjamin; Stokoe, David; Sampath, Deepak; Taylor, Barry S.; Evangelista, Marie; Shannon, Kevin.

In: Cell, Vol. 168, No. 5, 23.02.2017, p. 817-829.e15.

Research output: Contribution to journalArticle

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 2017, 'KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer', Cell, vol. 168, no. 5, pp. 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. https://doi.org/10.1016/j.cell.2017.01.020
Burgess, Michael R. ; Hwang, Eugene ; Mroue, Rana ; Bielski, Craig M. ; Wandler, Anica M. ; Huang, Benjamin J. ; Firestone, Ari J. ; Young, Amy ; Lacap, Jennifer A. ; Crocker, Lisa ; Asthana, Saurabh ; Davis, Elizabeth M. ; Xu, Jin ; Akagi, Keiko ; Le Beau, Michelle M. ; Li, Qing ; Haley, Benjamin ; Stokoe, David ; Sampath, Deepak ; Taylor, Barry S. ; Evangelista, Marie ; Shannon, Kevin. / KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer. In: Cell. 2017 ; Vol. 168, No. 5. pp. 817-829.e15.
@article{b3dd1fc7f36946648fc32d7ff784e91c,
title = "KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer",
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.",
keywords = "AML, KRAS, MEK inhibition, allelic imbalance, colorectal cancer, drug resistance",
author = "Burgess, {Michael R.} and Eugene Hwang and Rana Mroue and Bielski, {Craig M.} and Wandler, {Anica M.} and Huang, {Benjamin J.} and Firestone, {Ari J.} and Amy Young and Lacap, {Jennifer A.} and Lisa Crocker and Saurabh Asthana and Davis, {Elizabeth M.} and Jin Xu and Keiko Akagi and {Le Beau}, {Michelle M.} and Qing Li and Benjamin Haley and David Stokoe and Deepak Sampath and Taylor, {Barry S.} and Marie Evangelista and Kevin Shannon",
year = "2017",
month = "2",
day = "23",
doi = "10.1016/j.cell.2017.01.020",
language = "English (US)",
volume = "168",
pages = "817--829.e15",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "5",

}

TY - JOUR

T1 - KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer

AU - Burgess, Michael R.

AU - Hwang, Eugene

AU - Mroue, Rana

AU - Bielski, Craig M.

AU - Wandler, Anica M.

AU - Huang, Benjamin J.

AU - Firestone, Ari J.

AU - Young, Amy

AU - Lacap, Jennifer A.

AU - Crocker, Lisa

AU - Asthana, Saurabh

AU - Davis, Elizabeth M.

AU - Xu, Jin

AU - Akagi, Keiko

AU - Le Beau, Michelle M.

AU - Li, Qing

AU - Haley, Benjamin

AU - Stokoe, David

AU - Sampath, Deepak

AU - Taylor, Barry S.

AU - Evangelista, Marie

AU - Shannon, Kevin

PY - 2017/2/23

Y1 - 2017/2/23

N2 - 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.

AB - 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.

KW - AML

KW - KRAS

KW - MEK inhibition

KW - allelic imbalance

KW - colorectal cancer

KW - drug resistance

UR - http://www.scopus.com/inward/record.url?scp=85012927459&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85012927459&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2017.01.020

DO - 10.1016/j.cell.2017.01.020

M3 - Article

C2 - 28215705

AN - SCOPUS:85012927459

VL - 168

SP - 817-829.e15

JO - Cell

JF - Cell

SN - 0092-8674

IS - 5

ER -