Abstract 1692: PRMT5 inhibitor displays synergy with PARP inhibitor in bladder urothelial carcinoma models

Abstract Introduction: Approximately 30% of bladder cancers exhibit loss of methylthioadenosine phosphorylase (MTAP), a key enzyme in the methionine salvage pathway. This loss leads to an increase in its substrate, MTA, a metabolite that acts as an endogenous inhibitor of Protein arginine methyltransferase 5 (PRMT5) activity. PRMT5 uses S-adenosylmethionine (SAM) as a methyl donor to methylate various cellular substrates, including transcription factors, thereby regulating gene expression and DNA damage response (DDR) pathway. MTAP-deletion are suggested to be sensitive to PRMT5 inhibitors. We investigated the potential synergy between PRMT5 and PARP inhibitors in models of bladder cancer (BCa) harboring MTAP deletion. Methods: We investigated the effect of PRMT5 inhibitor AZ14209703 on viability of bladder cancer cell lines (MTAP-deficient: Umuc-3, RT4; MTAP-proficient: 5637, j82) and a patient-derived MTAP-deleted bladder cancer organoid model. Viability assays were performed after 72 hours and 10 days of treatment using the CellTiter-Glo and colony formation assays. Additionally, the synergy between the AZ14209703 and the PARP inhibitor (PARPi) olaparib was assessed through viability testing. Results: Cell viability assays conducted after 10 days of treatment revealed that MTAP-deficient cell lines (UMUC-3, RT4) are more sensitive to the PRMT5 inhibitor compared to MTAP-proficient cell lines (5637, J82). The 10-day IC50 values, measured by CellTiter-Glo, were as follows: MTAP-deficient cell lines RT4 (100 nM) and UMUC-3 (260 nM), and MTAP-proficient cell lines 5637 (2.24 µM). J82 exhibited even lower sensitivity, with treatment up to 10 µM failing to reduce viability by 50%. Similar results were obtained from colony formation assays, where the maximum dose of 4 µM for 10 days showed comparable outcomes. Additionally, the 10-day IC50 value for patient-derived MTAP-deficient organoids was 90 nM, as determined by CellTiter-Glo. The combination of PRMT5 inhibitor and olaparib demonstrated synergy in both MTAP-deficient and MTAP-proficient cell lines, as well as in patient-derived MTAP-deficient organoid models. This synergy was also observed in MTAP-proficient GBM cell lines (SNB19, LN229), an MTAP-proficient prostate cancer cell line (22RV1), an MTAP-deficient pancreatic cancer cell line (Capan-1), and an MTAP-proficient colorectal cancer cell line (HCT116). Conclusion: Our results highlight a promising new therapeutic approach for bladder cancer with potential application in the treatment of other cancers. The PRMT5 inhibitor AZ14209703 combined with olaparib offers a novel therapeutic strategy for MTAP-deficient tumors. Our ongoing studies are exploring the mechanisms of synergy and effects of PRMT5 inhibitors and combinations on immune-mediated killing of cancer cells. Citation Format: Maryam Ghandali, Connor Purcell, Leiqing Zhang, Lanlan Zhou, Dinara Ryspayeva, Maximilian Pinho-Schwermann, Brian K. Baker III, Paola Gyuliane, Benedito A. Carneiro, Wafik S. El-Deiry. PRMT5 inhibitor displays synergy with PARP inhibitor in bladder urothelial carcinoma models [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 1692.