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

doi:10.1016/j.cell.2017.01.020

Cited by 183Melanoma and MAPK PathwaysCancer Genomics and DiagnosticsProtein Kinase Regulation and GTPase Signaling

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

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Burgess, Michael R., Hwang, Eugene, Mroue, Rana, Bielski, Craig M., Wandler, Anica M., Huang, Benjamin J., Firestone, Ari J., Young, Amy +14 more·2017·Cell

DOI 10.1016/j.cell.2017.01.020PMC PMC5541948

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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 Kras G12D "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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In mutant KRAS cells, the presence of the wildtype allele can drive resistance to downstream pathway inhibitors including MEK.
“In mutant KRAS cells, the presence of the wildtype allele can drive resistance to downstream pathway inhibitors including MEK [108].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [108]

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“Increased copy number of KRAS has been corre ated with increased cell fitness in AML and CRC cells [41] and more aggressive and undifferentiated states in metastatic murine PDAC cells [45].”
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Integrated phosphoproteomics and transcriptional classifiers reveal hidden RAS signaling dynamics in multiple myeloma
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Two Distinct Structures of Membrane‐Associated Homodimers of GTP‐ and GDP‐Bound KRAS4B Revealed by Paramagnetic Relaxation Enhancement
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Analysis of RAS gene mutations in cytogenetically normal de novo acute myeloid leukemia patients reveals some novel alterations
Akram, A. M., Chaudhary, A., Kausar, H., Althobaiti, F., Abbas, A. S., Hussain, Z., Fatima, N., Zafar, E., Asif, D., Afzal, U., et al. (2021) · Saudi Journal of Biological Sciences · doi:10.1016/j.sjbs.2021.04.089 · Cited by 13 · see citing works

Fitness depends on KRAS imbalance
Romero, D. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2017.32
KRAS Allelic Imbalance: Strengths and Weaknesses in Numbers
Doherty, G. J., Kerr, E. M., & Martins, C. P. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.03.005 · Cited by 8 · see citing works
Loss of Wild-Type Kras is Associated with Enhanced Fitness and Increased Mitogen-Activated Protein Kinase Pathway Addiction in K-RasG12D Acute Myeloid Leukemia
Burgess, M. R., Hwang, E., Wandler, A. M., Asthana, S., Davis, E. M., Beau, M. M. L., Taylor, B. S., & Shannon, K. (2014) · Blood · doi:10.1182/blood.v124.21.907.907
Self-citation
Examining Genetic Balance May Help Lead to Improved Targeted Cancer Therapies
Schieszer, J. (2017)
P3.02-066 Wild-Type KRAS Mediates Growth Inhibition and Resistance to MEK Inhibitors through Dimerization with Mutant KRAS in Lung Adenocarcinoma
Ambrogio, C., Köhler, J., Zhou, Z., Wang, H., Paranal, R. M., Capelletti, M., Caffarra, C., Li, S., Lv, Q., Gondi, S. R., et al. (2017) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2017.09.1595 · Cited by 1 · see citing works

Authors: Burgess, M. R., Hwang, E., Mroue, R., Bielski, C. M., Wandler, A. M., Huang, B. J., Firestone, A. J., Young, A., Lacap, J. A., Crocker, L., Asthana, S., Davis, E. M., Xu, J., Akagi, K., Le Beau, M. M., Li, Q., Haley, B., Stokoe, D., Sampath, D., Taylor, B. S., Evangelista, M., & Shannon, K.
Affiliations: University of California, San Francisco (US)
Genentech (US)
Memorial Sloan Kettering Cancer Center (US)
University of Chicago (US)
The Ohio State University (US)
University of Michigan (US)
Corresponding author: Evangelista, Marie
Shannon, Kevin
ORCID: Wandler, Anica M.
Huang, Benjamin J.
Firestone, Ari J.
Young, Amy
Lacap, Jennifer A.
Xu, Jin
Akagi, Keiko
Li, Qing
Haley, Benjamin
Stokoe, David
Sampath, Deepak
Taylor, Barry S.
Evangelista, Marie
Shannon, Kevin
Venue: Cell
Publisher: Elsevier BV
Published: 2017-02
Volume: 168
Issue: 5
Pages: 817-829.e15
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2017.01.020
PMC: PMC5541948
OpenAlex: W2588657480
Cited by: 183
References: 51
Citations by year: 2026: 7 · 2025: 11 · 2024: 18 · 2023: 18 · 2022: 12 · 2021: 33 · 2020: 25 · 2019: 35 · 2018: 13 · 2017: 11
FWCI: 9.39
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 387 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: NIH (R01 CA180037, R37 CA72614, T32 CA108462, T32 CA128583, R01 CA207244, U54 OD202355, P30 CA0088748)
DOD NF1 Research Program (W81XWH-12-1-0157)
Rally Foundation for Childhood Cancer Research
The Truth 365
Leukemia and Lymphoma Society Specialized Center of Research (7019-04)
Ohio Supercomputer Center (PAS0425)
Cycle for Survival and the Josie Robertson Foundation (PF-14-146-01-LIB)
American Cancer Society – Hillcrest Committee (PF-14-070-01-TBG)
American Cancer Society (RP 10-078-01-TBE)
Damon Runyon Cancer Research Foundation (DRG-2149-13)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: KRAS, allelic imbalance, MEK inhibition, MAPK signaling, drug resistance, acute myeloid leukemia, colorectal cancer, tumor fitness, clonal evolution, HCT116 cells, CRISPR/Cas9, PD0325901
MeSH terms: Animals, Antineoplastic Agents, Benzamides, Diphenylamine, Humans, Mutation, Retroviridae, Colorectal Neoplasms, Leukemia, Myeloid, Acute, Proto-Oncogene Proteins p21(ras), Drug Resistance, Neoplasm, MAP Kinase Signaling System, Cell Line, Tumor, Mice, Clonal Evolution

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

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