1. Cancer Biology

Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6 dependent survival pathways

  1. S Michael Rothenberg
  2. Kyle Concannon
  3. Sarah Cullen
  4. Gaylor Boulay
  5. Alexa B Turke
  6. Anthony C Faber
  7. Elizabeth L Lockerman
  8. Miguel N Rivera
  9. Jeffrey A Engelman
  10. Shyamala Maheswaran
  11. Daniel A Haber  Is a corresponding author
  1. Massachusetts General Hospital, United States
https://doi.org/10.7554/eLife.06132
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Cite this article
  1. S Michael Rothenberg
  2. Kyle Concannon
  3. Sarah Cullen
  4. Gaylor Boulay
  5. Alexa B Turke
  6. Anthony C Faber
  7. Elizabeth L Lockerman
  8. Miguel N Rivera
  9. Jeffrey A Engelman
  10. Shyamala Maheswaran
  11. Daniel A Haber
(2015)
Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6 dependent survival pathways
eLife 4:e06132.
https://doi.org/10.7554/eLife.06132
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  3. Download .RIS

Abstract

Treatment of EGFR-mutant lung cancer with erlotinib results in dramatic tumor regression but it is invariably followed by drug resistance. In characterizing early transcriptional changes following drug treatment of mutant EGFR-addicted cells, we identified the stem cell transcriptional regulator SOX2 as being rapidly and specifically induced, both in vitro and in vivo. Suppression of SOX2 sensitizes cells to erlotinib-mediated apoptosis, ultimately decreasing the emergence of acquired resistance, whereas its ectopic expression reduces drug-induced cell death. We show that erlotinib relieves EGFR-dependent suppression of FOXO6, leading to its induction of SOX2, which in turn represses the pro-apoptotic BH3-only genes BIM and BMF. Together, these observations point to a physiological feedback mechanism that attenuates oncogene addiction-mediated cell death associated with the withdrawal of growth factor signaling and may therefore contribute to the development of resistance.

Article and author information

Author details

  1. S Michael Rothenberg

    Cancer Center, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Kyle Concannon

    Cancer Center, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Sarah Cullen

    Cancer Center, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Gaylor Boulay

    Cancer Center, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Alexa B Turke

    Cancer Center, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Anthony C Faber

    Cancer Center, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Elizabeth L Lockerman

    Cancer Center, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Miguel N Rivera

    Cancer Center, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Jeffrey A Engelman

    Cancer Center, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Shyamala Maheswaran

    Cancer Center, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Daniel A Haber

    Cancer Center, Massachusetts General Hospital, Charlestown, United States
    For correspondence
    dhaber@mgh.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Roger Davis, University of Massachusetts Medical School, United States

Ethics

Animal experimentation: All animal studies were conducted through Institutional Animal Care and Use Committee (IUCAC)-approved animal protocol 2010N000006 from the Massachusetts General Hospital. Mice were maintained in laminar flow units in aseptic condition and the care and treatment of all mice was in in accordance with institutional guidelines.

Version history

  1. Received: December 18, 2014
  2. Accepted: February 3, 2015
  3. Accepted Manuscript published: February 16, 2015 (version 1)
  4. Version of Record published: March 3, 2015 (version 2)

Copyright

© 2015, Rothenberg 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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  1. S Michael Rothenberg
  2. Kyle Concannon
  3. Sarah Cullen
  4. Gaylor Boulay
  5. Alexa B Turke
  6. Anthony C Faber
  7. Elizabeth L Lockerman
  8. Miguel N Rivera
  9. Jeffrey A Engelman
  10. Shyamala Maheswaran
  11. Daniel A Haber
(2015)
Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6 dependent survival pathways
eLife 4:e06132.
https://doi.org/10.7554/eLife.06132

Share this article

https://doi.org/10.7554/eLife.06132

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