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

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  • S Michael Rothenberg
    Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
  • Kyle Concannon
    Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
  • Sarah Cullen
    Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
  • Gaylor Boulay
    Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
  • Alexa B Turke
    Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
  • Anthony C Faber
    Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
  • Elizabeth L Lockerman
    Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
  • Miguel N Rivera
    Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
  • Jeffrey A Engelman
    Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
  • Shyamala Maheswaran
    Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
  • Daniel A Haber
    Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

Description

<jats:p>Treatment of <jats:italic>EGFR</jats:italic>-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 <jats:italic>BIM</jats:italic> and <jats:italic>BMF</jats:italic>. 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.</jats:p>

Journal

  • eLife

    eLife 4 2015-02-16

    eLife Sciences Publications, Ltd

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