Targeting the methionine-methionine adenosyl transferase 2A-S-adenosyl methionine axis for cancer therapy

Purpose of review In this review, we summarize the biological roles of methionine, methionine adenosyl transferase 2A (MAT2A) and S-adenosyl methionine (SAM) in methylation reactions during tumorigenesis. Newly emerged inhibitors targeting the methionine-MAT2A-SAM axis will be discussed. Recent findings SAM is the critical and global methyl-donor for methylation reactions regulating gene expression, and in mammalian cells, it is synthesized by MAT2A using methionine. Recent studies have validated methionine and MAT2A as metabolic dependencies of cancer cells because of their essential roles in SAM biosynthesis. MAT2A inhibition leads to synthetic lethality in methylthioadenosine-phosphorylase (MTAP)-deleted cancers, which accounts for 15% of all cancer types. Of note, remarkable progress has been made in developing inhibitors targeting the methionine-MAT2A-SAM axis, as the first-in-class MAT2A inhibitors AG-270 and IDE397 enter clinical trials to treat cancer. The methionine-MAT2A-SAM axis plays an important role in tumorigenesis by providing SAM as a critical substrate for abnormal protein as well as DNA and RNA methylation in cancer cells. Targeting SAM biosynthesis through MAT2A inhibition has emerged as a novel and promising strategy for cancer therapy.

Automated summary

This review summarizes the biological roles of methionine, methionine adenosyl transferase 2A (MAT2A), and S-adenosyl methionine (SAM) in methylation reactions during tumorigenesis. It discusses newly emerged inhibitors targeting the methionine-MAT2A-SAM axis. Recent studies have confirmed the essential roles of methionine and MAT2A in SAM biosynthesis and validated MAT2A as a metabolic dependency of cancer cells. Inhibition of MAT2A has shown synthetic lethality in MTAP-deleted cancers. Notably, significant progress has been made in developing inhibitors targeting the methionine-MAT2A-SAM axis, with first-in-class MAT2A inhibitors entering clinical trials. The methionine-MAT2A-SAM axis plays a critical role in tumorigenesis through providing SAM for abnormal protein, DNA, and RNA methylation in cancer cells. Targeting SAM biosynthesis through MAT2A inhibition has emerged as a novel and promising strategy for cancer therapy.