More than 200,000 women are diagnosed with breast cancer every year in the United States. About 80% of these cases are estrogen receptor positive (ER+), which is characterized by the up-regulation of ER signaling and downstream activation of cyclin-dependent kinases CDK4/6 and cyclin D1 (CCND1). Current lines of therapies include either endocrine therapies or CDK4/6 inhibitors, which have resulted in great improvement in the treatment of ER+ breast cancer. As expected, resistance to these therapies occurs over time and the development of additional therapeutic strategies is needed. Recently, the bromodomain and extra terminal (BET) proteins BRD3 and BRD4 were shown to be involved in the transcription of ER, and BET inhibitor (BETi) treatment can suppress ER-mediated signaling, offering a potential strategy to overcome endocrine resistance by further shutting down ER signaling regardless of ESR1 mutation status. However, it is still unclear if BRD3/4 are involved in the mechanisms of resistance to endocrine therapies, and whether BETi can potently inhibit the proliferation of ER+ breast cancer cells that are resistant to CDK4/6 inhibitors.

ZEN-3694 is an orally bioavailable small molecule bromodomain BET inhibitor currently undergoing clinical development in metastatic castration-resistant prostate cancer (mCRPC). ZEN-3694 showed efficacy in a panel of ER+ breast cancer cell lines and synergized with both tamoxifen and fulvestrant to inhibit proliferation and induce apoptosis. ZEN-3694 also showed activity in several models of resistance to ER+ breast cancer therapies, including tamoxifen, fulvestrant, estrogen-deprivation, as well as with CDK4/6 inhibitors. Analysis of the major pathways that were up-regulated upon acquisition of resistance to endocrine therapies and down-regulated by ZEN-3694 revealed several key players previously involved in developing resistance to endocrine therapies in breast cancer patients, including: inflammatory cytokines (IL-6, IL-1A, IL-1B), inducers and regulators of epithelial-mesenchymal transition (EMT) (Slug and ZEB-1), cancer stem cell marker (CD44), and angiogenesis regulators (VEGFA, VEGFC). Therefore, several of the transcriptional programs linked to the acquisition of resistance to endocrine therapies are regulated by BET proteins and inhibited by ZEN-3694.

Together, these results suggest that BET inhibitors have the potential to be a novel therapeutic strategy to treat ER+ breast cancer patients developing resistance to endocrine therapies as well as CDK4/6 inhibitors.

Citation Format: Kharenko OA, Patel RG, Jahagirdar R, Attwell S, Calosing C, Tsujikawa L, Campeau E, Lakhotia S, Hansen HC. The BET bromodomain inhibitors ZEN-3694 and ZEN-3309 targets several mechanisms of resistance to endocrine therapies in preclinical models of ER+ breast cancers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-06-07.