TY - JOUR
T1 - Synergy between androgen receptor antagonism and inhibition of mTOR and HER2 in breast cancer
AU - Gordon, Michael A.
AU - D'Amato, Nicholas C.
AU - Gu, Haihua
AU - Babbs, Beatrice
AU - Wulfkuhle, Julia
AU - Petricoin, Emanuel F.
AU - Gallagher, Isela
AU - Dong, Ting
AU - Torkko, Kathleen
AU - Liu, Bolin
AU - Elias, Anthony
AU - Richer, Jennifer K.
N1 - Funding Information:
Enzalutamide was provided by Astellas, Inc. and Medivation Inc. (Medivation, Inc. was acquired by Pfizer, Inc. in September 2016). The project was funded by DOD BCRP Clinical Translational Award BC120183 W81XWH-13-1-0090 to Jennifer K. Richer and A. Elias, R01 CA187733-01A1 to Jennifer K. Richer, and the Natural Science Foundation of Zhejiang Province, China partially supported HG (LY17H160058). The authors wish to acknowledge the University of Colorado Shared Resource (CCSG-P30CA046934). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2017 AACR.
PY - 2017/7
Y1 - 2017/7
N2 - The androgen receptor (AR) is widely expressed in breast cancer, and evidence suggests dependence on AR signaling for growth and survival. AR antagonists such as enzalutamide and seviteronel have shown success in preclinical models and clinical trials of prostate cancer and are currently being evaluated in breast cancer. Reciprocal regulation between AR and the HER2/PI3K/mTOR pathway may contribute to resistance to HER2- and mTOR-targeted therapies; thus, dual inhibition of these pathways may synergistically inhibit breast cancer growth. HER2+ and triple-negative breast cancer cell lines were treated with AR antagonist plus anti-HER2 mAb trastuzumab or mTOR inhibitor everolimus. Apoptosis, cell proliferation, and drug synergy were measured in vitro. Pathway component genes and proteins were measured by qRT-PCR, Western blot, and reverse phase protein array. In vivo, HER2+ breast cancer xenografts were treated with enzalutamide, everolimus, trastuzumab, and combinations of these drugs. AR antagonists inhibited proliferation of both HER2+ and TNBC cell lines. Combining AR antagonist and either everolimus or trastuzumab resulted in synergistic inhibition of proliferation. Dihydrotestosterone caused increased phosphorylation of HER2 and/or HER3 that was attenuated by AR inhibition. Everolimus caused an increase in total AR, phosphorylation of HER2 and/or HER3, and these effects were abrogated by enzalutamide. Growth of trastuzumab-resistant HER2+ xenograft tumors was inhibited by enzalutamide, and combining enzalutamide with everolimus decreased tumor viability more than either single agent. AR antagonists synergize with FDA-approved breast cancer therapies such as everolimus and trastuzumab through distinct mechanisms. Treatment combinations are effective in trastuzumab-resistant HER2+ breast cancer cells in vivo.
AB - The androgen receptor (AR) is widely expressed in breast cancer, and evidence suggests dependence on AR signaling for growth and survival. AR antagonists such as enzalutamide and seviteronel have shown success in preclinical models and clinical trials of prostate cancer and are currently being evaluated in breast cancer. Reciprocal regulation between AR and the HER2/PI3K/mTOR pathway may contribute to resistance to HER2- and mTOR-targeted therapies; thus, dual inhibition of these pathways may synergistically inhibit breast cancer growth. HER2+ and triple-negative breast cancer cell lines were treated with AR antagonist plus anti-HER2 mAb trastuzumab or mTOR inhibitor everolimus. Apoptosis, cell proliferation, and drug synergy were measured in vitro. Pathway component genes and proteins were measured by qRT-PCR, Western blot, and reverse phase protein array. In vivo, HER2+ breast cancer xenografts were treated with enzalutamide, everolimus, trastuzumab, and combinations of these drugs. AR antagonists inhibited proliferation of both HER2+ and TNBC cell lines. Combining AR antagonist and either everolimus or trastuzumab resulted in synergistic inhibition of proliferation. Dihydrotestosterone caused increased phosphorylation of HER2 and/or HER3 that was attenuated by AR inhibition. Everolimus caused an increase in total AR, phosphorylation of HER2 and/or HER3, and these effects were abrogated by enzalutamide. Growth of trastuzumab-resistant HER2+ xenograft tumors was inhibited by enzalutamide, and combining enzalutamide with everolimus decreased tumor viability more than either single agent. AR antagonists synergize with FDA-approved breast cancer therapies such as everolimus and trastuzumab through distinct mechanisms. Treatment combinations are effective in trastuzumab-resistant HER2+ breast cancer cells in vivo.
UR - http://www.scopus.com/inward/record.url?scp=85023751223&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-17-0111
DO - 10.1158/1535-7163.MCT-17-0111
M3 - Article
C2 - 28468774
AN - SCOPUS:85023751223
SN - 1535-7163
VL - 16
SP - 1389
EP - 1400
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 7
ER -