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• MAT2A sustains the survival of MTAP-deficient tumors, a genetic aberration present in ∼15% of all cancers. • Multiple new MAT2A inhibitors have reached the clinical testing stage as both a monotherapy or in combination. • Understanding which cancers benefit from MAT2A + PRMT5 inhibition is critical to advancing MAT2A inhibitors in the clinic. • New clinical trials have increased our knowledge of MAT2A inhibitor safety, risk, and efficacy. Metabolic and transcriptional reprogramming are crucial hallmarks of carcinogenesis that present exploitable vulnerabilities for the development of targeted anticancer therapies. Through controlling the balance of the cellular methionine (MET) metabolite pool, MET adenosyl transferase 2 alpha (MAT2A) regulates crucial steps during metabolism and the epigenetic control of transcription. The aberrant function of MAT2A has been shown to drive malignant transformation through metabolic addiction, transcriptional rewiring, and immune modulation of the tumor microenvironment (TME). Moreover, MAT2A sustains the survival of 5′-methylthioadenosine phosphorylase (MTAP)-deficient tumors, conferring synthetic lethality to cancers with MTAP loss, a genetic alteration that occurs in ∼15% of all cancers. Thus, the pharmacological inhibition of MAT2A is emerging as a desirable therapeutic strategy to combat tumor growth. Here, we review the latest insights into MAT2A biology, focusing on its roles in both metabolic addiction and gene expression modulation in the TME, outline the current landscape of MAT2A inhibitors, and highlight the most recent clinical developments and opportunities for MAT2A inhibition as a novel anti-tumor therapy.
Pulous et al. (Fri,) studied this question.