Abstract 4224: The pharmacological intervention of protein arginine methyltransferase 1 (PRMT1) leads to metastatic castration-resistant prostate cancer (mCRPC) repression through unique and significant androgen receptor (AR) downregulation and epige

AR based mechanisms drive resistance to first-line AR pathway inhibitor (ARPI) therapy and lead to poor survival in mCRPC, including AR amplification/mutations, and the emergence of novel splice variants such as AR-V7. The heterogeneity of AR genetic context and reactivation of AR-independent downstream genes, largely driven by cancer intrinsic epigenetic dysregulation further complicate mCRPC treatment. While AR degradation therapies such as proteolysis-targeting chimeras (PROTACs) show promise, they remain unsatisfied due to limited response and progression free survival (PFS) benefits in mCRPC patients with AR-V7 mutations or heterogeneous AR-resistant backgrounds. PRMT1 is the major type-I PRMT responsible for the asymmetric dimethylation of arginine residues on substrates such as H4R3 of histones or RG/RGG in proteins other than histones. Pharmacological intervention of PRMT1 can lead to cancer repression and benefit for long-term survival in multiple solid tumors in clinical trials, owing to its comprehensive mode-of-action (MoA) utilizing both epigenetic regulation of cancer gene expression and synthetic lethality to cancer intrinsic hallmarks such as DNA damage repair (DDR) and cell cycle arrest. Here we showed that PRMT1 is overexpressed in prostate cancer, particularly in advanced metastatic cases, well correlating with poorer prognosis of mCRPC. Inhibition of PRMT1 with CTS2190, a first-in-class (FIC), orally bioavailable, small molecular clinical investigational drug specific to PRMT1, results in significant AR degradation and tumor repression in various prostate cancer models, especially in AR-V7-positive mCRPC. CTS2190 not only decreases AR and asymmetric dimethylarginine (ADMA) levels, but also expression of prostate-specific antigen (PSA), MYC, and many downstream genes in AR signaling pathway in 22RV1 model, more effectively than docetaxel, enzalutamide, or even PROTAC targeting AR degradation. By co-modulating AR degradation and inducing DDR/cell cycle arrest, PRMT1 inhibition with CTS2190 shows promise as a potent monotherapy and as an ideal partner for combination with standard-of-care (SoC) treatments with different MoAs such as ARPI, chemo- or radio-therapies for mCRPC patients. CTS2190 could enhance antitumor activity with ARPI, docetaxel, topoisomerase I (TOP1) inhibitor or radiation, suggesting improved outcomes in enzalutamide-resistant mCRPC. Taken together, our findings highlight CTS2190 as a therapeutic agent, either alone or in combination, for a broader range of patients with ARPI-resistant mCRPC. CTS2190 is currently under evaluation in a phase I/II clinical trial, with an expansion cohort including mCRPC patients. Citation Format: Hui Shi, Yang Han, Xingnian Fu, Jiaxin Huang, Xinyue Duan, Yilin Liu, Youzhen Wang, Yuan Mi, Haiping Wu. The pharmacological intervention of protein arginine methyltransferase 1 (PRMT1) leads to metastatic castration-resistant prostate cancer (mCRPC) repression through unique and significant androgen receptor (AR) downregulation and epigenetic modulation [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 4224.