Abstract 4121: ORIC-101 overcomes resistance to diverse chemotherapeutics across cancer types

Abstract

Abstract Preclinical studies have shown that GR activation leads to decreased response to antimetabolites, taxanes, and platinum agents, while GR inhibition enhances therapeutic efficacy. The novel, selective GR antagonist ORIC-101 is under clinical evaluation in combination with anticancer therapies. In this study we set out to assess which cancer types and chemotherapeutics are responsive to combination with ORIC-101. Specifically, we employed caspase assays, in vitro and in vivo tumor growth inhibition studies, and transcriptional profiling in a panel of preclinical models spanning triple-negative breast, ovarian, non-small cell lung cancers, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, sarcoma, and renal cell carcinoma. We found that ORIC-101 reverses GR-mediated antiapoptosis effects towards diverse chemotherapeutics, including paclitaxel, gemcitabine, and cisplatin, across the seven cancer types. Furthermore, ORIC-101 completely overcomes GR-driven chemoprotection and tumor growth in colony formation assays in vitro and in xenograft studies in vivo. At the molecular level, transcriptional profiling and pathway enrichment analysis showed that ORIC-101 fully reverses GR-activated pathways that are directly involved in drug resistance, such as epithelial-to-mesenchymal transition and antiapoptosis, supporting a pan-cancer role of GR as a mediator of therapy resistance. Altogether, ORIC-101, a selective and potent GR antagonist, overcomes resistance to common chemotherapeutics across multiple cancer models. Clinical evaluation of ORIC-101 in combination with nab-paclitaxel is currently ongoing in advanced solid tumors. Citation Format: Haiying Zhou, Shravani Barkund, Aleksandr Pankov, Ganapati Hegde, Wayne Kong, Padmini Narayanan, Jessica D. Sun, Omar Kabbarah, Lori S. Friedman, Anneleen Daemen. ORIC-101 overcomes resistance to diverse chemotherapeutics across cancer types [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 4121.