Abstract LB427: The MTA-cooperative PRMT5 inhibitor ABSK131 exhibits potent activity and broad synergistic potential in MTAP-deleted cancer models

Abstract Background: Approximately 15% of all cancers harbor homozygous MTAP deletions, which are associated with poor prognoses. MTAP loss leads to the accumulation of 5′-methylthioadenosine (MTA), a competitive inhibitor of S-adenosylmethionine (SAM) binding to PRMT5. This has established MTA-cooperative PRMT5 as a synthetic lethal target in MTAP-deleted cancers. Despite advancements in selective PRMT5*MTA inhibitors, there remains a need for improvements in potency, selectivity, and brain penetration. ABSK131, developed by Abbisko, demonstrates a potential best-in-class profile in these aspects. Here, we evaluate the preclinical efficacy of ABSK131 in cancer cell lines of interest and its synergistic effects in combination with other therapeutic agents. Method: The anti-proliferative activity of ABSK131 was assessed using the CellTiter-Glo® assay in a panel of lung, pancreatic, and breast cancer cell lines. Combination studies were conducted to evaluate the synergy of ABSK131 with various therapeutic agents, including inhibitors targeting KRAS, MAT2A, PARP, and others, in both in vitro and in vivo settings. Results: Lung and pancreatic cancer cell lines with homozygous MTAP deletions exhibited high sensitivity to ABSK131, whereas breast cancer cell lines showed lower dependency. ABSK131 demonstrated broad synergistic activity when combined with the indicated agents in cellular proliferation assays. In mouse models, ABSK131 significantly enhanced anti-tumor efficacy when combined with other therapeutic agents, such as the MAT2A inhibitor IDE397. Conclusion: ABSK131 exhibits strong anti-tumor activity in MTAP-deleted lung and pancreatic cancer models and synergizes effectively with multiple therapeutic agents. These findings support the continued clinical development of ABSK131 as both a monotherapy and in combination regimens for MTAP-deleted cancers. Citation Format: Bin Shen, Qianqian Chen, Cong Li, Jie Wang, Jie Zhang, Manqi Liu, Zhui Chen, Nannan Zhang. The MTA-cooperative PRMT5 inhibitor ABSK131 exhibits potent activity and broad synergistic potential in MTAP-deleted cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB427.