Abstract 3822: ORIC-101 reverses a GR-driven EMT-like phenotype and sensitizes TNBC cells to chemotherapy
Authors: Haiying Zhou, Jessica Sun, Wayne Kong, Yosup Rew, Xiaohui Du, John Eksterowicz, Daqing Sun, Qiuping Ye, Omar Kabbarah, Valeria R. Fantin
Journal: Cancer Research (2019)

Abstract The Glucocorticoid Receptor (GR) is a member of the superfamily of nuclear hormone receptors that is activated by human cortisol and synthetic glucocorticoids such as dexamethasone (Dex). Upon ligand binding, GR translocates to the nucleus and regulates the expression of a wide spectrum of genes involved in diverse biological processes, including inflammation, immunity, metabolism, cell cycle, and differentiation. Dysregulated cortisol levels are associated with poor prognosis, drug resistance, and increased cancer recurrence. Multiple studies have shown that GR inhibition reverses resistance to chemotherapy in cancers of epithelial origin including prostate, bladder, renal, ovarian, pancreatic, and triple negative breast cancer (TNBC). We have recently reported the discovery of ORIC-101, a potent GR antagonist with a unique cytochrome P450 inhibition profile that makes this compound particularly suitable for combination with taxanes such as paclitaxel (Rew Y et al, 2018). Consistent with previous reports, our data showed that activation of GR promoted growth of TNBC cells in 3D culture conditions and protected TNBC cells from paclitaxel. Treatment with ORIC-101 fully reversed these effects. To understand the molecular basis of the observed GR-mediated chemotherapy resistance, we set out to isolate the pool of TNBC cells that escaped from paclitaxel treatment in the presence of Dex. Molecular profiling of these “chemotherapy escapees” pointed to a number of glucocorticoid-regulated biological pathways, including basal stem cell lineage genes and mesenchymal markers, suggesting the acquisition of an EMT-like phenotype in chemo-resistant cells. In support of this finding, we found using ChIP-seq analysis that GR directly bound within the promoter/enhancer regions of well-established EMT genes such as SNAI2 and FN1, and regulated their expression in response to Dex treatment. Functionally, RNAi-mediated knockdown of SNAI2 partially restored sensitivity to paclitaxel, suggesting that the GR-driven EMT phenotype contributes to paclitaxel resistance in TNBC cells. Consistent with the in vitro observations, immunohistochemical analysis showed that GR activation upregulated the levels of both basal stem cell and mesenchymal markers in “chemotherapy escapees” from paclitaxel-treated TNBC xenografts. Importantly oral administration of ORIC-101 fully blocked these effects. Altogether, we found that activation of GR drove an EMT-like phenotype in TNBC cells in vitro and in vivo. ORIC-101 reversed these effects and sensitized TNBC cells to chemotherapy. Our findings thus provide mechanistic insights into the role of GR as a mediator of therapy resistance in TNBC. Clinical evaluation is being planned to assess the therapeutic potential of ORIC-101 in combination with standard-of-care chemotherapeutic agents. Citation Format: Haiying Zhou, Jessica Sun, Wayne Kong, Yosup Rew, Xiaohui Du, John Eksterowicz, Daqing Sun, Qiuping Ye, Omar Kabbarah, Valeria R. Fantin. ORIC-101 reverses a GR-driven EMT-like phenotype and sensitizes TNBC cells to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3822.