Abstract 1770: HM100760, a potent and selective MAT2A inhibitor, demonstrates a synergistic anticancer effect when combined with a PRMT5 inhibitor in MTAP-deleted cancer

Abstract Methionine adenosyltransferase 2A (MAT2A) is the primary enzyme responsible for the synthesis of S-adenosylmethionine (SAM) from methionine and ATP. SAM serves as a universal methyl donor in various transmethylation and biosynthetic pathways. Recently, MAT2A has emerged as a synthetic lethal target in cancers harboring deletions of the methylthioadenosine phosphorylase (MTAP) gene, which occurs in approximately 15% of all cancers. MTAP deletion results in the accumulation of methylthioadenosine (MTA), which partially inhibits protein arginine methyltransferase 5 (PRMT5). Inhibition of MAT2A in MTAP-deficient cancers leads to reduced intracellular SAM levels, which sensitizes PRMT5 to further inhibition. Likewise, this interplay offers a strong rationale for the combinational use of MAT2A inhibitors, which block SAM synthesis, with MTA-cooperative PRMT5 inhibitors. Here, the biochemical activity of HM100760, a potent and selective MAT2A inhibitor, was evaluated in terms of its effect on MAT2A enzymatic function, cellular SAM levels, and symmetric dimethylarginine (SDMA) regulation. HM100760 exhibited strong inhibition of MAT2A catalytic activity, leading to significant reductions in SAM and SDMA levels in HCT116 MTAP-null cells. In addition, HM100760 displayed robust anti-proliferative effects across a range of MTAP-deficient cancer cell lines, including those derived from pancreatic, bladder, and non-small cell lung cancer (NSCLC). In preclinical in vivo studies, HM100760 demonstrated dose-dependent tumor growth inhibition in multiple MTAP-null xenograft models, including HCT116, KP-4, and LU99. Moreover, combining HM100760 with a PRMT5 inhibitor in the endogenous MTAP-null LU99 xenograft model resulted in a synergistic antitumor effect, outperforming monotherapy treatments. Notably, HM100760 achieved this therapeutic efficacy without causing significant body weight loss or observable clinical symptoms, underscoring its favorable safety profile. In conclusion, HM100760 is considered a promising therapeutic candidate for MTAP-deleted cancers. It exhibits potent antitumor activity as a monotherapy and demonstrates enhanced efficacy when combined with a PRMT5 inhibitor. Ongoing preclinical studies aim to further characterize HM100760’s therapeutic potential and broaden its application in MTAP-deficient cancer treatment. Citation Format: Minjeong Kim, Eun Joo Kwak, Miyoung Lee, Soonki Park, Hobin Lim, Soyeon Kim, Hye Sun Han, Seung Hyun Jung, Jooyun Byun, Sang Hyun Lee, Young Gil Ahn. HM100760, a potent and selective MAT2A inhibitor, demonstrates a synergistic anticancer effect when combined with a PRMT5 inhibitor in MTAP-deleted cancer [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 1770.