Targeting the p300/CBP epigenetic pathway to overcome hormone therapy resistance in advanced prostate cancer

Purpose/Objective(s): Despite improvements in the treatment of advanced prostate cancer, there remains a major unmet need for further treatment options in the setting of metastatic castration-resistant prostate cancer (mCRPC). Recent evidence has pinpointed androgen receptor (AR) co-activators, such as p300/CREB binding protein (CBP), as potential therapeutic targets. Here, we describe the impact of a novel small molecule inhibitor of the p300/CBP bromodomain, FT-6876, in preclinical models of mCRPC. Materials/Methods: FT-6876 is a potent inhibitor of the bromodomains of CBP and p300 with high selectivity against other bromodomain-containing proteins (Caligiuri et al. Proceedings: AACR Annual Meeting 2020; Cancer Research. DOI: 10.1158/1538-7445.AM2020-3079). FT-6876 was tested, both alone and in combination with enzalutamide, in a panel of enzalutamide-sensitive and enzalutamide-resistant human prostate cancer cell lines, including LNCaP, LN95, and CS2. A Snail-inducible system, which confers enzalutamide resistance, in both LNCaP and LN95 lines, was also used. To test the effect of FT-6876 in inhibiting prostate cancer growth in vitro, 2D colony forming assays and 3D spheroid assays were performed. RT-qPCR and multi-omics analysis were performed to assess changes in gene and protein expression. To test the effects of FT-6876 in physiologic settings, an ex vivo murine pulmonary metastasis assay (PuMA) as well as a patient-derived xenograft (PDX) model were used. Results: FT-6876 treatment resulted in concentration-dependent growth inhibition of all tested enzalutamide-sensitive and -resistant cell lines. Treated cells showed decreased expression of several key prostate cancer genes, including KLK3 (PSA), TMPRSS2, and MYC. A multi-omics approach using proteomics, acetylomics, and RNA-Seq illuminated the global landscape of alterations in epigenetic and downstream signaling pathways induced by FT-6876. Changes were observed in both enzalutamide-sensitive and -resistant models. Finally, FT-6876 reduced metastatic growth in the PuMA model and induced tumor stasis in a patient-derived xenograft model of prostate cancer resistant to enzalutamide. Conclusion: Overall, we demonstrate that inhibiting the p300/CBP axis with the novel bromodomain inhibitor FT-6876 could be an effective therapeutic approach for both enzalutamide-sensitive and enzalutamide-resistant prostate cancer models. The safety and tolerability of FT-7051, an oral p300/CBP inhibitor related to FT-6876, is currently being evaluated in the Courage Study (NCT04575766), a first-in-human phase 1 study in men with mCRPC. Citation Format: Emily L. Chen, Nathan Hawkey, Beatrice C. Thomas, Kathryn E. Ware, Daniella Runyambo, Maureen Caligiuri, Erik Wilker, Erik J. Soderblom, M. Arthur Moseley III, Sylvie M. Guichard, Andrew J. Armstrong, Jason A. Somarelli. Targeting the p300/CBP epigenetic pathway to overcome hormone therapy resistance in advanced prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P204.