Abstract 6862: Preclinical evaluation of drugs for the treatment of MTAP-deficient cancers

Abstract 5-Methylthioadenosine phosphorylase (MTAP), a key enzyme in the methionine salvage pathway that plays a vital role in cell apoptosis, proliferation, differentiation and inflammatory response, is frequently deleted in human cancers, approximately 15% of total tumors, including 53% of glioblastomas, 33% of bladder cancers, 26% of pancreatic cancers, and other tumor types. Deficiencies in MTAP lead to the accumulation of 5'-methylthioadenosine (MTA), which subsequently inhibits protein arginine methyl transferase 5 (PRMT5). This mechanism facilitates the development of therapeutics that selectively target MTA-bound PRMT5 (PRMT5: MTA) in MTAP-deficient tumors, while sparing normal tissues expressing wild-type MTAP. Numerous studies have demonstrated that MTAP-deficient cells exhibit heightened sensitivity to methionine depletion and inhibitors of purine synthesis, rendering PRMT5 and MAT2A promising therapeutic targets for MTAP-deficient tumors. In this study, we presented our preclinical research focusing on MTAP related models. We assessed the mRNA expression of MTAP in over 700 human cancer cell lines and more than 1, 400 patient-derived xenograft (PDX) models. Subsequently, with in vitro viability assay we showed that the two PRMT5 inhibitors, GSK3326595 and MRTX1719 exhibited strong anti-proliferative effects against MTAP-deficient cells. In vivo, we proved that GSK3326595 showed a significant antitumor activity against MTAP-deficient models. Additionally, immunohistochemistry (IHC) staining was performed to assess the MTAP protein levels in forty PDX models, which covering pancreatic, colon, and bladder cancers types. Models harboring moderate PRMT5 expression but lacking MTAP were selected for efficacy study with MRTX1719. This selective PRMT5 inhibitor developed a superior anti-tumor effect, achieving a tumor growth inhibition of over 100% after three weeks of treatment. In summary, our findings may advance the development of novel therapeutic strategies for MTAP-deficient cancers. Citation Format: Qin Li, Jie Yang, Feifei Fan, Jian Xiang, Yajie Xiong, Ying Tong, Shuai Zhao, Qingyang Gu. Preclinical evaluation of drugs for the treatment of MTAP-deficient cancers [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 6862.