biostudies-literatureUnknown4Rothenberg SMHoward Hughes Medical InstituteNational Institute of Dental and Craniofacial ResearchNational Institutes of HealthTreatment 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.eLifehttps://www.ebi.ac.uk/biostudies/studies/S-EPMC4384750biostudies-literatureInhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6-dependent survival pathways.PMC4384750K08DE020139RO1 CA207186Rothenberg SMTurke ABFaber ACMaheswaran SConcannon KHaber DACullen SBoulay GLockerman ELRivera MNEngelman JAfalseInhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6-dependent survival pathways.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.2015-01-01T00:00:00Z2015 Feb2024-11-12T05:22:49.462Z2019-03-27T01:49:21ZS-EPMC43847502568621910.7554/eLife.06132