eLife (Feb 2015)

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

  • S Michael Rothenberg,
  • Kyle Concannon,
  • Sarah Cullen,
  • Gaylor Boulay,
  • Alexa B Turke,
  • Anthony C Faber,
  • Elizabeth L Lockerman,
  • Miguel N Rivera,
  • Jeffrey A Engelman,
  • Shyamala Maheswaran,
  • Daniel A Haber

DOI
https://doi.org/10.7554/eLife.06132
Journal volume & issue
Vol. 4

Abstract

Read online

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.

Keywords