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
Marcho, L. M.; Coss, C. C.; Xu, M.; Datta, J.; Manouchehri, J. M.; Cherian, M. A.
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ObjectiveSeventy percent of newly diagnosed breast cancers are estrogen receptor- positive and HER2/neu negative [1]. First-line treatments incorporate endocrine therapy and cyclin-dependent kinase 4/6 inhibitors [2]. However, therapy resistance occurs in most patients [3-5]. Hence, there is an urgent need for effective second-line treatments. We previously showed that the potent estrogen receptor-{beta} agonists, OSU-ERb-12 and LY500307, synergized with the selective estrogen receptor modulator, tamoxifen, in vitro. Furthermore, we showed that these compounds inhibited endocrine-resistant and cyclin-dependent kinase 4/6-inhibitor-resistant estrogen receptor -positive cell lines in vitro [6]. Here, we used fulvestrant- and abemaciclib-resistant T47D-derived cell line xenografts to determine the efficacy of the combination of OSU-ERb-12 and LY500307 with tamoxifen in vivo. ResultsDespite 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.
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