Oric-101 Comprehensively Inhibits Glucocorticoid Pathways To Overcome Therapeutic Resistance In Pan-Cancer Models

Abstract Preclinical studies have established a role for the Glucocorticoid Receptor (GR) in mediating resistance to both anti-hormonal therapies and conventional chemotherapies in epithelial cancers. Studies in breast cancer models have established that the chemoprotective effect afforded by GR activation is facilitated, at least partially, through upregulation of genes involved in anti-apoptosis, epithelial-to-mesenchymal transition (EMT), and metastasis - thus suggesting that GR inhibition may enhance therapeutic responses. A novel GR antagonist, ORIC-101, is in early clinical development in combination with nab-paclitaxel in advanced solid tumors (NCT03928314). We set out to understand the transcriptional consequences of activating GR in a panel of 9 triple negative breast cancer (TNBC), 12 non-small cell lung cancer (NSCLC) and 12 pancreatic ductal adenocarcinoma (PDAC) cell lines, covering three indications likely to be encountered in clinical trials. Cell lines were selected to capture the transcriptional variability across subtypes of each indication, and transcriptome profiling using RNA-sequencing was performed on these cell lines after treatment with the synthetic glucocorticoid dexamethasone (Dex) in the presence or absence of ORIC-101. We present a comprehensive evaluation of GR-mediated signaling across 3 key indications and 33 cancer cell lines. Overall, Dex resulted in transcriptional regulation of hundreds of genes. While there was a high degree of variation in the specific genes regulated by GR across TNBC, NSCLC, and PDAC models, a set of 11 genes emerged as consistently upregulated by GR, termed the “GR activation signature”. The addition of ORIC-101 completely reverted the expression of these 11 signature genes back to vehicle condition levels. We further validated a subset of signature genes as ORIC-101 pharmacodynamic biomarkers that may be used to inform target engagement status within a patient population in clinical trials. Despite the high degree of variability in the GR-driven transcriptional programs at the gene level, pathway enrichment analysis revealed biological convergence towards a common set of GR regulated pathways including EMT, apoptosis, stemness, hypoxia, inflammation/immune regulation, and extracellular matrix. These molecular processes associated with GR were observed across TNBC, NSCLC, and PDAC cell lines, suggesting a common drug resistance mechanism of GR across the cancer types. Importantly, ORIC-101 completely reversed these Dex-induced changes at both the gene and the pathway level. Our results not only elucidate the direct mechanism of GR-mediated chemotherapy resistance but also showcase the ability of ORIC-101 to revert all transcriptional changes caused by GR activation. Citation Format: Aleksandr Pankov, Haiying Zhou, Shravani Barkund, Ganapati Hegde, Padmini Narayanan, Omar Kabbarah, Lori S. Friedman, Anneleen Daemen. ORIC-101 comprehensively inhibits glucocorticoid pathways to overcome therapeutic resistance in pan-cancer models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4120.