Abstract 6920: Targeting the AR co-activator CBP/p300 in metastatic castration-resistant prostate cancer (mCRPC)

Abstract Purpose: Standard treatment for metastatic castration-resistant prostate cancer (mCRPC) includes androgen receptor (AR) pathway inhibitors (ARPIs), such as androgen deprivation therapy or enzalutamide. Despite prolonged survival with ARPI therapies, resistance is nearly universal, highlighting the urgent need to identify new resistance mechanisms and therapeutic targets. Methods: We combined systems-level and experimental approaches to identify and test actionable network nodes linked to ARPI resistance as therapeutic vulnerabilities in prostate cancer. Systems-level analyses were performed using weighted gene co-expression network analysis and Bayesian network inference. Networks were overlaid with experimental data, including ENCODE ChIP-Seq data. The in vitro efficacy of pocebrodib was evaluated in a series of enzalutamide-sensitive and -resistant prostate cancer cell lines using CellTiter-Glo, colony forming assays and 3D spheroid assays. The in vivo activity of pocebrodib was evaluated in patient-derived xenografts. Proteomics and acetylomics was used to interrogate the potential mechanisms of action for pocenbrodib. Results were validated by RT-qPCR, western blotting and flow cytometry. Knockdown studies were performed using non-targeting and SCP2-targeting siRNAs. Results: Multi-layer network inference pinpointed the CREB binding protein (CBP)/p300 complex as a key regulatory node associated with patient outcomes and ARPI resistance. Consistent with this observation, preclinical testing of the CBP/p300 inhibitor, pocebrodib, demonstrated efficacy in both enzalutamide-sensitive and -resistant lines in vitro, with IC50s of ∼1 μM. Cell growth inhibition was accompanied by downregulation of AR activity, as indicated by RNA-Seq and RT-qPCR. Pocenbrodib also demonstrated tumor growth inhibition of both enzalutamide-sensitive and -resistant patient-derived xenografts and a durable response in a patient with ARPI-resistant prostate cancer as part of the Phase I COURAGE study. Proteomics and acetylomics identified differential acetylation of both histone and non-histone proteins, including a subset of histone acetylation events altered in enzalutamide-resistant cells that are restored upon treatment with pocenbrodib. These analyses also identified enrichment of fatty acid metabolism proteins, including the sterol carrier protein 2 (SCP2) and fatty acid synthase (FASN), suggesting CBP inhibition may cause cells to sense loss of acetyltransferase activity as a reduction in free acetyl-coA, leading to alteration in fatty acid metabolism as a feedback response. Conclusion: Inhibition of the CBP/p300 axis by pocenbrodib is a promising new approach to treat ARPI-resistant prostate cancer. Future studies are aimed at clinical evaluation of pocenbrodib and exploration of downstream signaling axes to identify key biomarkers of response to pocenbrodib. Citation Format: Ananya Dutta, Beatrice C. Thomas, Pelumi Olawuni, Erik Soderblom, Eric Schadt, Bonnie Dougherty, Andrew J. Armstrong, Jason A. Jason A. Somarelli. Targeting the AR co-activator CBP/p300 in metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6920.