title: Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6-dependent survival pathways.
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.
authors: Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
authors: S Michael
authors: SM
authors: Rothenberg
authors: Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
authors: Kyle
authors: K
authors: Concannon
authors: Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
authors: Sarah
authors: S
authors: Cullen
authors: Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
authors: Gaylor
authors: G
authors: Boulay
authors: Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
authors: Alexa B
authors: AB
authors: Turke
authors: Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
authors: Anthony C
authors: AC
authors: Faber
authors: Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
authors: Elizabeth L
authors: EL
authors: Lockerman
authors: Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
authors: Miguel N
authors: MN
authors: Rivera
authors: Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
authors: Jeffrey A
authors: JA
authors: Engelman
authors: Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
authors: Shyamala
authors: S
authors: Maheswaran
authors: Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
authors: Daniel A
authors: DA
authors: Haber
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D008565:Membrane Proteins / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D055748:SOXB1 Transcription Factors / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; C486655:BMF protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C478770:FOXO6 protein, human; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors
keywords: EGFR mutations; SOX2; human; human biology; lung cancer; medicine; mouse; resistance; targeted cancer therapy