Synergy between androgen receptor antagonism and inhibition of mTOR and HER2 in breast cancer

The androgen receptor (AR) is widely expressed in breast cancer (BC) and evidence suggests dependence on AR signaling for growth and survival. AR antagonists such as enzalutamide and seviteronel have shown success in pre-clinical models and clinical trials of prostate cancer, and are currently being evaluated in BC. 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 BC growth. HER2+ and triple-negative BC cell lines were treated with AR antagonist plus anti-HER2 monoclonal antibody 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+ BC 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 BC therapies such as everolimus and trastuzumab through distinct mechanisms. Treatment combinations are effective in trastuzumab-resistant HER2+ BC cells in vivo.

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