Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6-dependent survival pathways
2015
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
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.
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