Abstract 4268: The allosteric MAT2A inhibitor IDE397 uniquely exploits metabolic liabilities associated with MTAP deletion to perturb DNA replication and repair

Methylthioadenosine phosphorylase (MTAP) is co-deleted with the tumor suppressor CDKN2A in approximately 15% of solid tumors. Loss of MTAP blocks cellular 1-carbon salvage pathway activity due to an inability to convert MTA into adenine and methionine. Accumulation of MTAP’s substrate, MTA, and coincident depletion of the MTAP’s products, adenine and methionine precursors, results in two distinct targetable vulnerabilities: direct S-Adenosyl methionine (SAM)-competitive inhibition of the essential methyltransferase Protein arginine methyltransferase 5 (PRMT5), and reduced capacity for sufficient nucleotide synthesis required to support tumor cell DNA replication and repair. MAT2A is the rate-limiting enzyme for SAM synthesis in tumor cells, and its position at the intersection of methyltransferase activity and 1-carbon metabolism indicates pharmacological suppression of MAT2A has the unique potential to exploit both vulnerabilities conferred by MTAP deletion (MTAPdel). IDE397 is an allosteric MAT2A inhibitor designed to deliver anti-tumor activity selectively in patients harboring MTAPdel tumors and has demonstrated clinical activity. Here, we have deployed label and label-free profiling of IDE397-dependent effects on tumor cell metabolism paired with genome-wide assessments of cellular methyltransferase activity to evaluate key determinants of IDE397 anti-tumor activity. IDE397 selectively perturbed de novo nucleoside/nucleotide biosynthesis in MTAPdel cells via depletion of homocysteine pools and disruption of methionine cycle/folate cycle integration. Global analyses of RNA splicing, chromatin accessibility, and DNA methylation indicated that IDE397 effectively suppressed PRMT5 methyltransferase activity, while other essential SAM-dependent processes were maintained. These observations indicate that MTAP loss confers a dual dependency on MAT2A activity for sufficient SAM biosynthesis to both support 1-carbon metabolism-associated DNA repair capacity in the absence of MTA recycling, and to ameliorate direct inhibition of PRMT5 by MTA. Furthermore, broad preservation of SAM-dependent methyltransferase activity in the presence of IDE397 suggests a hierarchy among methyltransferases for SAM consumption. Observations of adaptive compensation within distinct methyltransferase pathways, such as polyamine synthesis, suggest this hierarchy is dynamic and orchestrated. The metabolic liabilities arising from MAT2A inhibition in MTAP deleted cancer cells provide a mechanistic rationale for unique therapeutic opportunities for IDE397 as a single-agent and in combination which are now being evaluated in patients (NCT04794699 and NCT05975073). Citation Format: Damien Garbett, Arjun A. Rao, Marcus M. Fischer, John Vivian, Khristina Magallanes, Natalie Bresnahan, Pari Lanham, Atul Rathore, Austin Li, Rebeca M. Choy, J Carl Schultz, Scott R. Tyler, Angelica Gonzalez-Sanchez, Zhipeng Fang, Kelly Trego, Briana Marinoni, Yuchen Bai, Peter Teriete, Christian R. Frey, Michael A. White, Claire L. Neilan. The allosteric MAT2A inhibitor IDE397 uniquely exploits metabolic liabilities associated with MTAP deletion to perturb DNA replication and repair [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 4268.