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
Affiliations
S Michael Rothenberg
Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
Kyle Concannon
Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
Sarah Cullen
Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
Gaylor Boulay
Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, United States
Alexa B Turke
Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
Anthony C Faber
Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
Elizabeth L Lockerman
Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
Miguel N Rivera
Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, United States
Jeffrey A Engelman
Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
Shyamala Maheswaran
Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
Daniel A Haber
Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States; Howard Hughes Medical Institute, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States
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.