TY - JOUR TI - Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6-dependent survival pathways AU - Rothenberg, S Michael AU - Concannon, Kyle AU - Cullen, Sarah AU - Boulay, Gaylor AU - Turke, Alexa B AU - Faber, Anthony C AU - Lockerman, Elizabeth L AU - Rivera, Miguel N AU - Engelman, Jeffrey A AU - Maheswaran, Shyamala AU - Haber, Daniel A A2 - Davis, Roger VL - 4 PY - 2015 DA - 2015/02/16 SP - e06132 C1 - eLife 2015;4:e06132 DO - 10.7554/eLife.06132 UR - https://doi.org/10.7554/eLife.06132 AB - 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. KW - targeted cancer therapy KW - EGFR mutation KW - SOX2 KW - resistance KW - lung cancer JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -