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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.

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Time course of SOX2 induction by quantitative immunofluorescencemicroscopy.The data for the 24 hr time points are the same as in Figure 2A. p-values are shown for thecomparison of mean SOX2 fluorescence of each treated population to DMSO(Student's t-test, unequal variances, N =341–3485, % SOX2+ is shown). Source data are included asFigure2—source data 2.DOI:http://dx.doi.org/10.7554/eLife.06132.007
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fig1s4: Time course of SOX2 induction by quantitative immunofluorescencemicroscopy.The data for the 24 hr time points are the same as in Figure 2A. p-values are shown for thecomparison of mean SOX2 fluorescence of each treated population to DMSO(Student's t-test, unequal variances, N =341–3485, % SOX2+ is shown). Source data are included asFigure2—source data 2.DOI:http://dx.doi.org/10.7554/eLife.06132.007

Mentions: SOX2 encodes a master transcriptional regulator, implicated in stem cell maintenanceand iPS cell generation. It is also required for upper aerodigestive tractdevelopment, and is known to be amplified in a subset of esophageal and squamous lungcancers, although it has not been previously implicated in lung adenocarcinomas,including the subset driven by mutant EGFR (Elliset al., 2004; Gontan et al., 2008;Bass et al., 2009). Remarkably, SOX2expression following exposure of HCC827 cells to erlotinib was transient, peaking at24 hr after exposure to therapeutic levels of the drug (Figure 1D). Thereafter, SOX2 expression returned to basal levelsdespite continued erlotinib treatment in surviving cells (Figure 1D, Figure1—figure supplement 4).


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)

Time course of SOX2 induction by quantitative immunofluorescencemicroscopy.The data for the 24 hr time points are the same as in Figure 2A. p-values are shown for thecomparison of mean SOX2 fluorescence of each treated population to DMSO(Student's t-test, unequal variances, N =341–3485, % SOX2+ is shown). Source data are included asFigure2—source data 2.DOI:http://dx.doi.org/10.7554/eLife.06132.007
© Copyright Policy
Related In: Results  -  Collection

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

fig1s4: Time course of SOX2 induction by quantitative immunofluorescencemicroscopy.The data for the 24 hr time points are the same as in Figure 2A. p-values are shown for thecomparison of mean SOX2 fluorescence of each treated population to DMSO(Student's t-test, unequal variances, N =341–3485, % SOX2+ is shown). Source data are included asFigure2—source data 2.DOI:http://dx.doi.org/10.7554/eLife.06132.007
Mentions: SOX2 encodes a master transcriptional regulator, implicated in stem cell maintenanceand iPS cell generation. It is also required for upper aerodigestive tractdevelopment, and is known to be amplified in a subset of esophageal and squamous lungcancers, although it has not been previously implicated in lung adenocarcinomas,including the subset driven by mutant EGFR (Elliset al., 2004; Gontan et al., 2008;Bass et al., 2009). Remarkably, SOX2expression following exposure of HCC827 cells to erlotinib was transient, peaking at24 hr after exposure to therapeutic levels of the drug (Figure 1D). Thereafter, SOX2 expression returned to basal levelsdespite continued erlotinib treatment in surviving cells (Figure 1D, Figure1—figure supplement 4).

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