Identification of CTX-30916 as a novel antagonist of progesterone receptor signaling pathways

Breast cancer is the most commonly diagnosed cancer in women and the second leading cause of cancer related death in women. Progesterone is a major mitogen in the adult human mammary epithelium that, in addition to estrogen, is a key driver of breast cancer cell proliferation. Activated PR signaling through MAPK-driven phosphorylation of the progesterone receptor (PR) is also an important driver of breast cancer stem cells. PR expression is associated with the presence of estrogen receptor-alpha (ESR1) mutations that are constitutively active and linked to resistance in the clinic in response to aromatase inhibitors, antiestrogens and CDK4/6 inhibitors. Thus, PR may play a role in tumor relapse and resistance in the clinic and blocking both estrogen and progesterone receptors would likely be an effective approach in 2L treatment for patients with advanced breast cancer. There is great interest in evaluating antiprogestins in the clinic in combination with antiestrogens or CDK4/6 inhibitors. Apristor®, an extended release formulation of onapristone, a full antagonist of PR, that has efficacy in multiple in vivo and in vitro models in combination with antiestrogestins and CDK4/6 inhibitors, is currently being evaluated in several human clinical trials. In this study we have examined the in vitro properties of CTX-30916, a novel mono-N-desmethyl analog of onapristone. CTX-30916 binds potently to PR and acts as an antagonist in cell-based transfection assays. CTX-30916 displays selectivity against other steroid receptors in binding assays and is also a potent inhibitor of T47D breast cancer cell proliferation. Interestingly, CTX-30916 leads to a unique co-regulator binding pattern in the Microarray Assay for Real-time Co-regulator-Nuclear receptor interaction (MARCoNI) assay compared with onapristone and mifepristone indicating that the co-regulator peptide-PR interaction landscape is different between the various antiprogestins. These data suggest that CTX-30916 binding to PR leads to a distinct receptor conformation and antagonizes PR signaling pathways in cancer through a unique mechanism of action compared to other antiprogestins. Citation Format: Deepak Lala, Tasir Haque. Identification of CTX-30916 as a novel antagonist of progesterone receptor signaling pathways [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 2625.