Abstract 4486: The MTA-cooperative PRMT5 inhibitor CTS3497 alone and in synergy with mechanism-based combination targeted therapies for the treatment of MTAP -deleted cancers.

Abstract Homozygous deletion of chr9p21/CDKN2A/MTAP occurs in approximately 15% of human cancers and represents a high unmet medical need. Protein arginine methyltransferase 5 (PRMT5), a key member of the type-II PRMT family, has emerged as a synthetic-lethal target for MTAPnull cancers. The MTA-cooperative PRMT5 inhibitor CTS3497, currently in Phase I/II trials (NCT06971523), exhibited potent cell growth inhibition with a low single-digit nM IC50 and 171-fold high selectivity for MTAPnull over isogenic MTAPwt cells. In vivo, CTS3497 led to tumor inhibition or deep regression in MTAPnull xenograft models of various lineages, notably MTAPnull orthotopic glioma. The brain penetration property of CTS3497 underscores its therapeutic potential for both primary brain tumors and brain metastases. Mechanism-based therapeutic combinations were explored to improve response and defeat emergent resistance of standard of care (SOC) targeted agents. Co-targeting type I and type II PRMTs with CTS2190 (currently in Phase II trial, NCT06224387) and CTS3497 demonstrated strong synergy against MTAPnull tumors in vitro and in vivo, especially in intractable pancreatic cancer. Moreover, the synergy of CTS2190 and CTS3497 was also significant in MTAPnull cells that were established acquired resistance to PRMT5 inhibitors, suggesting the potential combinational use of the dual PRMT inhibitors post PRMT5 targeted therapy. In addition, combination of CTS3497 and osimertinib (EGFR-TKI) enhanced anti-tumor efficacy and suppressed acquired resistance to osimertinib in MTAPnullEGFRmut lung cancer xenografts. Furthermore, CTS3497 effectively reversed resistance to adagrasib (KRASG12C) in an adagrasib-resistant MTAPnull model, resulting in profound tumor regression without regrowth even after discontinuation of treatment. CTS3497 also synergized with Bcl-2/xL inhibitors by promoting apoptosis, more prominently in MTAPnull BCL2L1amp tumor cells. In summary, CTS3497 exhibits strong antitumor activity alone and in combination with clinically feasible targeted agents including but not limited to type I PRMT, EGFR, KRAS and Bcl-2/xL inhibitors. CTS3497 represents a promising synthetic-lethal precision medicine for patients with MTAP-deficient cancers either as a single agent or in combination with rational combination partners. Particularly, combination of CTS3497 with CTS2190, a type I PRMT inhibitor, may provide a potential solution for patients post PRMT5 targeted therapy. Citation Format: Yilin Liu, Xinyue Duan, Hui Shi, Qiugeng Ouyang, Jiaxin Huang, Meng Wang, Xingnian Fu, Yiqin Wang, Guoliang Xu, Haiping Wu. The MTA-cooperative PRMT5 inhibitor CTS3497 alone and in synergy with mechanism-based combination targeted therapies for the treatment of MTAP-deleted cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4486.