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Hyperactivation of ERK by multiple mechanisms is toxic to RTK-RAS mutation-driven lung adenocarcinoma cells

  1. Arun M Unni  Is a corresponding author
  2. Bryant Harbourne
  3. Min Hee Oh
  4. Sophia Wild
  5. John R Ferrarone
  6. William W Lockwood  Is a corresponding author
  7. Harold Varmus  Is a corresponding author
  1. Weill Cornell Medicine, United States
  2. British Columbia Cancer Agency, Canada
Research Article
  • Cited 24
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Cite this article as: eLife 2018;7:e33718 doi: 10.7554/eLife.33718

Abstract

Synthetic lethality results when mutant KRAS and EGFR proteins are co-expressed in human lung adenocarcinoma (LUAD) cells, revealing the biological basis for mutual exclusivity of KRAS and EGFR mutations. We have now defined the biochemical events responsible for the toxic effects by combining pharmacological and genetic approaches and to show that signaling through extracellular signal-regulated kinases (ERK1/2) mediates the toxicity. These findings imply that tumors with mutant oncogenes in the RAS pathway must restrain the activity of ERK1/2 to avoid toxicities and enable tumor growth. A dual specificity phosphatase, DUSP6, that negatively regulates phosphorylation of (P)-ERK is up-regulated in EGFR- or KRAS-mutant LUAD, potentially protecting cells with mutations in the RAS signaling pathway, a proposal supported by experiments with DUSP6-specific siRNA and an inhibitory drug. Targeting DUSP6 or other negative regulators might offer a treatment strategy for certain cancers by inducing the toxic effects of RAS-mediated signaling.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2 and Figure 2-supplemental figure 1 in the Methods section and/or in the text.

The following previously published data sets were used

Article and author information

Author details

  1. Arun M Unni

    Meyer Cancer Center, Weill Cornell Medicine, New York, United States
    For correspondence
    aru2001@med.cornell.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0530-1470
  2. Bryant Harbourne

    Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Min Hee Oh

    Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Sophia Wild

    Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. John R Ferrarone

    Meyer Cancer Center, Weill Cornell Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. William W Lockwood

    Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, Canada
    For correspondence
    wlockwood@bccrc.ca
    Competing interests
    The authors declare that no competing interests exist.
  7. Harold Varmus

    Meyer Cancer Center, Weill Cornell Medicine, New York, United States
    For correspondence
    varmus@med.cornell.edu
    Competing interests
    The authors declare that no competing interests exist.

Funding

Cancer Research Society

  • William W Lockwood

National Institutes of Health

  • Harold Varmus

Meyer Cancer Center

  • Harold Varmus

Terry Fox Research Institute

  • William W Lockwood

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Jonathan A. Cooper, Fred Hutchinson Cancer Research Center, United States

Publication history

  1. Received: November 21, 2017
  2. Accepted: November 26, 2018
  3. Accepted Manuscript published: November 26, 2018 (version 1)
  4. Version of Record published: December 18, 2018 (version 2)

Copyright

© 2018, Unni et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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