Potent Estrogen Receptor β Agonists with Inhibitory Activity In Vitro, Fail to Suppress Xenografts of Endocrine-Resistant Cyclin-dependent Kinase 4/6 inhibitor-Resistant Breast Cancer Cells

Mathew A. Cherian ^1* Lynn M. Marcho ¹ Christopher Coss ² Menglin Xu ¹ Jharna Datta ¹ Jasmine M. Manouchehri ¹

• ¹ Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States
• ² College of Pharmacy, The Ohio State University, Columbus, Ohio, United States

Objective: Seventy percent of newly diagnosed breast cancers are estrogen receptor-α positive and HER2/neu negative. First-line treatments incorporate endocrine therapy and cyclin-dependent kinase 4/6 inhibitors. However, therapy resistance occurs in most patients. Hence, there is an urgent need for effective second-line treatments. We previously showed that the potent estrogen receptor-β agonists, OSU-ERβ-12 and LY500307, synergized with the selective estrogen receptor modulator, tamoxifen, in vitro. Furthermore, we showed that these compounds inhibited endocrine-resistant and cyclindependent kinase 4/6-inhibitor-resistant estrogen receptor α-positive cell lines in vitro. Here, we used fulvestrant-and abemaciclib-resistant T47D-derived cell line xenografts to determine the efficacy of the combination of OSU-ERβ-12 and LY500307 with tamoxifen in vivo.Results: Despite efficacy in vitro, treatments failed to reduce xenograft tumor volumes. Hence, we conclude that this treatment strategy lacks direct cancer cell-intrinsic cytotoxic efficacy in vivo.