Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6 dependent survival pathways
- Massachusetts General Hospital, United States
Abstract
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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Animal experimentation: All animal studies were conducted through Institutional Animal Care and Use Committee (IUCAC)-approved animal protocol 2010N000006 from the Massachusetts General Hospital. Mice were maintained in laminar flow units in aseptic condition and the care and treatment of all mice was in in accordance with institutional guidelines.
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© 2015, Rothenberg et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6 dependent survival pathways
eLife 4:e06132.
https://doi.org/10.7554/eLife.06132
