Homozygous deletions in the gene encoding methylthioadenosine phosphorylase (MTAP) occur in ∼10% of patients with cancer, including up to 45% in some tumor types, and may be associated with poor prognosis. MTAP deficiency causes accumulation of its catabolic target methylthioadenosine (MTA) that outcompetes S-adenosyl methionine (SAM) for binding to protein arginine methyltransferase 5 (PRMT5), partially inhibiting PRMT5 activity as a posttranslational regulator of a variety of critical cellular functions. Prior anticancer treatments developed to target PRMT5 exhibited high rates of dose-limiting hematologic toxicities because of a lack of selectivity for tumor cells. More recently, several agents have been developed that exploit the vulnerability of MTAP-deleted cancer cells to further inhibition of the PRMT5 pathway, selectively inducing synthetic lethality in those cancer cells. MTA-cooperative PRMT5 inhibitors such as BMS-986504/MRTX1719 and AMG 193 target the PRMT5-MTA complex, whereas inhibitors of the SAM synthetase methionine adenosyl transferase 2A, 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.
Rodon et al. (2026) studied this question.