Abstract 6544: Targeting resistance mechanisms to AR-targeted therapy in prostate cancer through inhibition of CREBBP/EP300
Authors: Dougherty Bonnie V. , Thomas Beatrice C. , Walsh Alice M. , Calvo Veronica , Ware Kathryne E. , Armstrong Andrew J. , Renstrup Jens , Somarelli Jason A. , Schadt Eric E. 
Published: March 2024

Abstract
Standard initial treatment for men with metastatic prostate cancer involves targeting the androgen receptor (AR) with androgen deprivation therapy or androgen-receptor signaling inhibitors. Resistance eventually develops, such as through AR-activating alterations, leaving few targeted options for patients. Here, we utilize data from 4,509 prostate cancer patients with longitudinal clinical and DNA/RNA sequencing data to elucidate mechanisms of resistance and identify potential therapeutic vulnerabilities in resistant disease. By constructing comprehensive regulatory networks, termed hybrid networks, built across different disease stages, combining features from WGCNA, causal mediation analysis, probabilistic causal network inference, and public knowledge graphs, we uncover subnetworks strongly associated with disease progression and resistance. These subnetworks reflect biological processes for cell cycle, E2F, DNA repair, MYC, and AR, comprehensively identifying broad transcriptional changes that drive disease progression and resistance.
Selected subnetwork scores, derived from RNA expression, were significantly associated with outcomes in both the hormone-sensitive and castration-resistant settings, demonstrating that the subnetworks capture early and late resistance. The hybrid networks identified the transcriptional co-activators CREBBP and EP300 as key modulators of these subnetworks, suggesting that targeting CREBBP/EP300 may be effective in treating both early and late-stage disease. Prostate cancer cell lines were treated with FT-6876, a small molecule inhibitor of CREBBP/EP300, and growth inhibition was measured in both enzalutamide sensitive and resistant cell lines, covering a wide range of resistance mechanisms. The selected subnetworks were enriched for genes down-regulated following treatment with FT-6876, suggesting that targeting CREBBP/P300 addresses multiple resistance-related pathways. Differential changes in protein abundance and protein acetylation between enzalutamide sensitive and resistant cell lines identified changes in fatty acid metabolism as a common, downstream event in response to treatment with FT-6876, suggesting an additional mechanism for response to FT-6876.
Together, our integrated theoretical and experimental analyses support the hypothesis that targeting CREBBP/EP300 may provide therapeutic benefits to prostate cancer patients. Further, the subnetworks identified may serve as mechanistically-informed biomarkers for identifying patients who may benefit from inhibition of CREBBP/EP300.
Citation Format: Bonnie V. Dougherty, Beatrice C. Thomas, Alice M. Walsh, Veronica Calvo, Kathryne E. Ware, Andrew J. Armstrong, Jens Renstrup, Jason A. Somarelli, Eric E. Schadt. Targeting resistance mechanisms to AR-targeted therapy in prostate cancer through inhibition of CREBBP/EP300 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6544.