Limits...
Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6-dependent survival pathways.

Rothenberg SM, Concannon K, Cullen S, Boulay G, Turke AB, Faber AC, Lockerman EL, Rivera MN, Engelman JA, Maheswaran S, Haber DA - Elife (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, 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.

Show MeSH

Related in: MedlinePlus

SOX2 expression modulates erlotinib-induced apoptosis.Left panel, quantitative immunofluorescence analysis showing expressionof SOX2 (x-axis) and cleaved caspase-3 (y-axis) in PC9 cells transfectedwith siCTRL (blue) or siSOX2 (red) and treated with erlotinib (N =2452–3792). Knockout of SOX2 results in decreased SOX2 expressionand increased cleaved caspase-3. Right panels, representativeimmunofluorescence images from erlotinib-treated cells showing DAPI(blue), SOX2 (red), and cleaved-caspase-3 (green) staining. Source dataare included as Figure 5—source data 2.DOI:http://dx.doi.org/10.7554/eLife.06132.031
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4384750&req=5

fig5s2: SOX2 expression modulates erlotinib-induced apoptosis.Left panel, quantitative immunofluorescence analysis showing expressionof SOX2 (x-axis) and cleaved caspase-3 (y-axis) in PC9 cells transfectedwith siCTRL (blue) or siSOX2 (red) and treated with erlotinib (N =2452–3792). Knockout of SOX2 results in decreased SOX2 expressionand increased cleaved caspase-3. Right panels, representativeimmunofluorescence images from erlotinib-treated cells showing DAPI(blue), SOX2 (red), and cleaved-caspase-3 (green) staining. Source dataare included as Figure 5—source data 2.DOI:http://dx.doi.org/10.7554/eLife.06132.031

Mentions: 10.7554/eLife.06132.029Figure 5—source data 2.Raw immunofluorescence data for quantitation of SOX2 andcleaved caspase-3 costaining in PC9 cells transfected withsiCTRL or siSOX2 in Figure5—figure supplement 2.


Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6-dependent survival pathways.

Rothenberg SM, Concannon K, Cullen S, Boulay G, Turke AB, Faber AC, Lockerman EL, Rivera MN, Engelman JA, Maheswaran S, Haber DA - Elife (2015)

SOX2 expression modulates erlotinib-induced apoptosis.Left panel, quantitative immunofluorescence analysis showing expressionof SOX2 (x-axis) and cleaved caspase-3 (y-axis) in PC9 cells transfectedwith siCTRL (blue) or siSOX2 (red) and treated with erlotinib (N =2452–3792). Knockout of SOX2 results in decreased SOX2 expressionand increased cleaved caspase-3. Right panels, representativeimmunofluorescence images from erlotinib-treated cells showing DAPI(blue), SOX2 (red), and cleaved-caspase-3 (green) staining. Source dataare included as Figure 5—source data 2.DOI:http://dx.doi.org/10.7554/eLife.06132.031
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4384750&req=5

fig5s2: SOX2 expression modulates erlotinib-induced apoptosis.Left panel, quantitative immunofluorescence analysis showing expressionof SOX2 (x-axis) and cleaved caspase-3 (y-axis) in PC9 cells transfectedwith siCTRL (blue) or siSOX2 (red) and treated with erlotinib (N =2452–3792). Knockout of SOX2 results in decreased SOX2 expressionand increased cleaved caspase-3. Right panels, representativeimmunofluorescence images from erlotinib-treated cells showing DAPI(blue), SOX2 (red), and cleaved-caspase-3 (green) staining. Source dataare included as Figure 5—source data 2.DOI:http://dx.doi.org/10.7554/eLife.06132.031
Mentions: 10.7554/eLife.06132.029Figure 5—source data 2.Raw immunofluorescence data for quantitation of SOX2 andcleaved caspase-3 costaining in PC9 cells transfected withsiCTRL or siSOX2 in Figure5—figure supplement 2.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, 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.

Show MeSH
Related in: MedlinePlus