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Antiestrogen Fulvestrant Enhances the Antiproliferative Effects of Epidermal Growth Factor Receptor Inhibitors in Human Non–Small-Cell Lung Cancer  Edward.

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Presentation on theme: "Antiestrogen Fulvestrant Enhances the Antiproliferative Effects of Epidermal Growth Factor Receptor Inhibitors in Human Non–Small-Cell Lung Cancer  Edward."— Presentation transcript:

1 Antiestrogen Fulvestrant Enhances the Antiproliferative Effects of Epidermal Growth Factor Receptor Inhibitors in Human Non–Small-Cell Lung Cancer  Edward B. Garon, MD, Richard J. Pietras, MD, PhD, Richard S. Finn, MD, Naeimeh Kamranpour, BS, Sharon Pitts, BS, Diana C. Márquez-Garbán, MD, Amrita J. Desai, BS, Judy Dering, PhD, Wylie Hosmer, MD, Erika M. von Euw, PhD, Steven M. Dubinett, MD, Dennis J. Slamon, MD, PhD  Journal of Thoracic Oncology  Volume 8, Issue 3, Pages (March 2013) DOI: /JTO.0b013e31827d525c Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

2 FIGURE 1 In vitro sensitivity to erlotinib, fulvestrant, and the combination of both agents—54 NSCLC cell lines with IC50 for (A) erlotinib and (B) fulvestrant using ATCC-recommended media are presented in μM. C, IC50 values for fulvestrant in lines grown in phenol red-free media with DCC-FBS are shown. D, In phenol red-free media with DCC-FBS, sensitivity to combined erlotinib 1 μM and fulvestrant 2.5 μM is shown, with fulvestrant (white bars), erlotinib (gray bars), and the combination (black bars). Lines are arranged in descending order of the difference in IC50 between combination treatment and erlotinib, with boxes around cell lines with IC50 for fulvestrant of less than 5 μM. Error bars indicate standard error based on duplicate experiments. NSCLC, non–small-cell lung cancer; ATCC, American Type Culture Collection; IC50, concentration leading to 50% inhibition; FBS, fetal bovine serum; DCC, dextran-coated charcoal-filtered. Journal of Thoracic Oncology 2013 8, DOI: ( /JTO.0b013e31827d525c) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

3 FIGURE 2 Baseline expression of hormone receptor genes and proteins. A and B, For each cell line, protein levels of ERα, ERβ, PR-A, PR-B, aromatase, and tubulin were evaluated by established Western blot methods. Green bars by the cell line name indicate an IC50 of less than 5 μM in the ATCC-recommended media, whereas red bars by the cell line name indicate an IC50 of less than 5 μM in phenol red-free media with DCC-FBS. C, In a subset of evaluated cell lines, baseline gene expression data were available, and expression of a hormonal gene set is shown with an X marking lines with an IC50 of less than 5 μM. ATCC, American Type Culture Collection; DCC, dextran-coated charcoal-filtered; FBS, fetal bovine serum; PR, progesterone receptor; IC50, concentration leading to 50% inhibition. Journal of Thoracic Oncology 2013 8, DOI: ( /JTO.0b013e31827d525c) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

4 FIGURE 3 In vivo evaluation of gefitinib, fulvestrant, and the combination of both drugs in human A549 xenografts in nude mice. A, Ovariectomized nude mice with estradiol supplements and A549 tumors received 21 days of vehicle control (squares), gefitinib (circles) 160 mg daily, fulvestrant (triangles) 5 mg SQ weekly, or the combination of gefitinib and fulvestrant (diamonds). B, The same model was assessed with erlotinib (circles) as the EGFR TKI. Mice were treated with assigned therapy for 21 days, and then followed for 60 days to assess outcomes. EGFR TKI, epidermal growth receptor factor tyrosine kinase inhibitors; SQ, subcutaneously. Journal of Thoracic Oncology 2013 8, DOI: ( /JTO.0b013e31827d525c) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

5 FIGURE 4 In vitro effects of erlotinib, fulvestrant, or the combination of both agents on EGFR TKI-resistant, EGFR-mutant lung cancer cell proliferation and viability. Growth curves of the H1975 line after 6 days of treatment with erlotinib (diamonds), fulvestrant (squares), or the combination of the two drugs (triangles) are shown at the concentrations listed. A, Combination index for the combination at constant ratio. B, Apoptosis at 72 hours was assessed in H1975 cells with no therapy (white), erlotinib 1 μM (stripes), fulvestrant 200 nM (black), or the combination (checked). Error bars indicate standard error based on duplicate experiments. EGFR TKI, epidermal growth receptor factor tyrosine kinase inhibitors. Journal of Thoracic Oncology 2013 8, DOI: ( /JTO.0b013e31827d525c) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

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