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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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Distribution of FOXO6 vs SOX2 nuclear staining.(A) HCC827 cells were left untreated or were treated with0.1 µM erlotinib for 24 hr. Cells were stained with goat anti-SOX2and rabbit anti-FOXO6 primary antibodies, followed by anti-goat-AlexaFluor 488 (green) and anti-rabbit-Alexa Fluor 647 (red) secondaryantibodies (and DAPI in blue). FOXO6 appears to colocalize (yellow in theleftmost panels) with SOX2 in cells with the highest expression of thelatter, especially in erlotinib-treated cells (arrows). (B)Quantitative immunofluorescence analysis demonstrates a positivecorrelation between FOXO6 and SOX2 nuclear fluorescence in individualcells (Correlation coefficient R untreated/treated = 0.7/0.5, N= 1700/835 cells). Source data are included as Figure7—source data 2.DOI:http://dx.doi.org/10.7554/eLife.06132.041
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fig7s3: Distribution of FOXO6 vs SOX2 nuclear staining.(A) HCC827 cells were left untreated or were treated with0.1 µM erlotinib for 24 hr. Cells were stained with goat anti-SOX2and rabbit anti-FOXO6 primary antibodies, followed by anti-goat-AlexaFluor 488 (green) and anti-rabbit-Alexa Fluor 647 (red) secondaryantibodies (and DAPI in blue). FOXO6 appears to colocalize (yellow in theleftmost panels) with SOX2 in cells with the highest expression of thelatter, especially in erlotinib-treated cells (arrows). (B)Quantitative immunofluorescence analysis demonstrates a positivecorrelation between FOXO6 and SOX2 nuclear fluorescence in individualcells (Correlation coefficient R untreated/treated = 0.7/0.5, N= 1700/835 cells). Source data are included as Figure7—source data 2.DOI:http://dx.doi.org/10.7554/eLife.06132.041

Mentions: 10.7554/eLife.06132.038Figure 7—source data 2.Raw immunofluorescence data for quantitation of SOX2 andFOXO6 costaining in HCC827 cells in Figure 7—figure supplement3.


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)

Distribution of FOXO6 vs SOX2 nuclear staining.(A) HCC827 cells were left untreated or were treated with0.1 µM erlotinib for 24 hr. Cells were stained with goat anti-SOX2and rabbit anti-FOXO6 primary antibodies, followed by anti-goat-AlexaFluor 488 (green) and anti-rabbit-Alexa Fluor 647 (red) secondaryantibodies (and DAPI in blue). FOXO6 appears to colocalize (yellow in theleftmost panels) with SOX2 in cells with the highest expression of thelatter, especially in erlotinib-treated cells (arrows). (B)Quantitative immunofluorescence analysis demonstrates a positivecorrelation between FOXO6 and SOX2 nuclear fluorescence in individualcells (Correlation coefficient R untreated/treated = 0.7/0.5, N= 1700/835 cells). Source data are included as Figure7—source data 2.DOI:http://dx.doi.org/10.7554/eLife.06132.041
© Copyright Policy
Related In: Results  -  Collection

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

fig7s3: Distribution of FOXO6 vs SOX2 nuclear staining.(A) HCC827 cells were left untreated or were treated with0.1 µM erlotinib for 24 hr. Cells were stained with goat anti-SOX2and rabbit anti-FOXO6 primary antibodies, followed by anti-goat-AlexaFluor 488 (green) and anti-rabbit-Alexa Fluor 647 (red) secondaryantibodies (and DAPI in blue). FOXO6 appears to colocalize (yellow in theleftmost panels) with SOX2 in cells with the highest expression of thelatter, especially in erlotinib-treated cells (arrows). (B)Quantitative immunofluorescence analysis demonstrates a positivecorrelation between FOXO6 and SOX2 nuclear fluorescence in individualcells (Correlation coefficient R untreated/treated = 0.7/0.5, N= 1700/835 cells). Source data are included as Figure7—source data 2.DOI:http://dx.doi.org/10.7554/eLife.06132.041
Mentions: 10.7554/eLife.06132.038Figure 7—source data 2.Raw immunofluorescence data for quantitation of SOX2 andFOXO6 costaining in HCC827 cells in Figure 7—figure supplement3.

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