The Role of Methionine Adenosyltransferase 2A in Tumorigenesis and the Development of Its Inhibitors

Methionine adenosyltransferase (MAT) catalyzes the formation of S-adenosylmethionine (SAM), serving as the primary methyl group donor in mammalian cells, from methionine and adenosine triphosphate (ATP). MAT family consists of MAT1A, MAT2A and MAT2B. MAT2A is responsible for the synthesis of SAM in extrahepatic normal tissues and cancer tissues, MAT1A is solely responsible for SAM synthesis in normal liver tissue and bile duct epithelial cells, while MAT2B has no catalytic activity. Accumulated evidence illuminates that MAT2A has a cancerogenic role by mediating cancer metabolism, functioning as a transcriptional cofactor. MAT2A, therefore, has been known as a site of therapeutic vulnerability for cancer. Particularly, after finding that MAT2A inhibition and methylthioadenosine phosphorylase (MTAP) loss are synergistically lethal, more attention has been paid to the promising discovery of diverse kinds of MAT2A inhibitors, which mainly include substrate-competitive inhibitors and allosteric inhibitors, in an attempt to treat MTAP-deleted tumors and explore the strategy of combined therapy. This review summarizes the oncogenic mechanisms of MAT2A and the development of MAT2A inhibitors, with a focus on the potential strategies of applying MAT2A inhibitors, hoping to identify a novel target for precisive cancer treatment and new strategies for drug combination.