MAT2A (Methionine Adenosyltransferase 2A)

Our findings demonstrate that MTAP deletion is an infrequent but genomically coherent event in solid tumors, characterized by a canonical 9p21 co-deletion pattern. This real-world analysis underscores the importance of comprehensive genomic profiling to identify patients who may benefit from emerging MTAP-directed therapies.

MTAP activity was also measured across a panel of cancer cell lines to determine intracellular MTAP levels and to complement whole-blood measurements. This approach enables real-time evaluation of MTAP function and drug response in μL volumes of lysate, providing a direct biological or clinical platform for tracking targeted MTAP therapies.

Consequently, PGG can induce pyroptosis by cleaving GSDME in various tumor cells and suppress tumor cell growth through enhancing anti-tumor immune response. Collectively, our findings reveal that MAT2A is an essential metabolic regulator of pyroptosis, and PGG could potentially boost anti-tumor immunity by targeting MAT2A.

Here, we trace the evolution of MAT2A inhibitors from early substrate-competitive molecules to allosteric inhibitors now in clinical evaluation. We discuss the design of next-generation inhibitors with improved potency, selectivity, and pharmacokinetic properties, including central nervous system penetration.

We further evaluate methionine-restricted (MR) strategies and MAT2A inhibition as emerging interventions capable of reconditioning the TME and synergizing with immunotherapy. Finally, from a novel and integrative perspective, we map the evolving clinical landscape of methionine-targeted therapies and outline future translational directions, aiming to provide a comprehensive framework for understanding its therapeutic potential in cancer.

AG-270 showed lack of cancer specificity in combination with rMETase when tested on both cancer and normal cells. The present results contrast with numerous chemotherapy agents, which in combination with rMETase are synergistic on cancer cells but not on normal cells. The present findings suggest that MAT2A inhibition affects crucial metabolic pathways in normal as well as cancer cell types and thus AG-270 may not be suitable as a cancer-specific therapeutic strategy.

This study developed two novel MAT2A-targeted PET tracers: the 18F-labeled [18F]1d, derived from AZ-28, demonstrates rapid tumor uptake (equilibrium ∼20 min), high tumor-to-muscle ratio, and specific MAT2A binding in H1975 xenografts, though it shows some bone uptake due to defluorination; the 68Ga-labeled [68Ga]1s, based on AG-270, retains high MAT2A affinity (IC50 = 6.23 nM) and exhibits superior pharmacokinetics─low liver uptake, renal clearance, and high cellular internalization (80%)...Molecular docking confirms key interactions with the MAT2A allosteric site. Both tracers provide promising tools for solid tumor diagnosis, treatment monitoring, and precision oncology.

MAT2A also elevates aerobic glycolysis in osteosarcoma cells through the PARN-PI3K-AKT pathway, while pharmacological inhibition of MAT2A reduces glycolysis, SRF and PARN expression, and tumor growth in vitro and in vivo. These findings identify a previously unrecognized regulatory mechanism linking MAT2A to transcriptional control and metabolic reprogramming, and highlight MAT2A as a promising therapeutic target for osteosarcoma.

INSM1 overexpression in SH-SY-5Y cells upregulated neuroendocrine and thyroid hormone-related genes (CHGA, CHGB, DDC, NCAM1, DIO3, TH), while suppressing genes involved in cell cycle (RRM, CDC25A), methionine metabolism (AHCY, MAT2A), transcriptional regulation (MYBL2, EZH2), and oncogenic signaling (ALK, LINC011667). These findings suggest that INSM1 promotes NB aggressiveness by sustaining a neuroendocrine progenitor-like phenotype through metabolic-epigenetic coupling.

MAT2A, BCAT1 and GCLM were selected for small interfering RNA experiments and the results exhibited that apoptosis rates significantly promoted in HL60/R when MAT2A, BCAT1 or GCLM were interfered. An integrative analysis of proteomic and metabolomic data revealed significant disruptions in amino acid metabolism in HL60/R cells, including the metabolic pathways of alanine, aspartate and glutamate, cysteine and methionine, as well as glutathione metabolism.

MTA-cooperative PRMT5 inhibitors such as BMS-986504/MRTX1719 and AMG 193 target the PRMT5-MTA complex, while inhibitors of the SAM synthetase methionine adenosyl transferase 2A (MAT2A), such as IDE397, deprive PRMT5 of its methyl donor SAM. In this review article, we summarize the mechanisms of action, preclinical data, and clinical data available thus far for these novel classes of oncology precision medicine and discuss potential future directions relevant to MTAP deletion as a promising synthetic lethal vulnerability for cancer therapy.

Our work uncovers a neutrophil-driven, MAT2A-dependent activation of methionine metabolism as a critical metabolic mechanism fueling liver metastasis in BC. These findings position the TAN-MAT2A-methionine axis as a promising therapeutic target for the treatment of BCLM.