Synthetic Lethality Between PRMT5 and MTAP as a Cancer Therapeutic

Abstract

Synthetic lethality arises when the combined inhibition of two genes results in cell death. Scientists have begun using this phenomenon in cancer treatments to target certain cancers. This review focuses specifically on the synthetic lethal relationship between MTAP and PRMT5, and how this relationship is used in cancer treatments. MTAP breaks down MTA, a natural inhibitor of PRMT5. In certain cancers, MTAP is often deleted as a result of cell mutation. When MTAP is deleted in these cancers, the buildup of MTA partially inhibits PRMT5, causing the cell to become highly dependent on the remaining PRMT5. This vulnerability in cancer cells has led to therapies that specifically target the remaining PRMT5 in MTAP-deleted cancer cells, allowing the treatment to destroy MTAP-deleted cancer cells while limiting damage to healthy cells. Currently, MTA-cooperative PRMT5 inhibitors are going through phase I/II clinical trials. Although several MTA-cooperative PRMT5 inhibitors have exhibited dose-limiting toxicities like nausea and fatigue, early studies still show promising signs for a treatment with the potential to selectively target MTAP-deleted cancer cells while doing minimal damage to surrounding tissue.