Targeting the MTAP-PRMT5 axis: from synthetic lethality to emerging therapeutic opportunities

Homozygous deletion of MTAP, one of the most frequent somatic copy-number alterations in cancer, creates a context of synthetic lethal vulnerability. MTAP loss leads to the accumulation of MTA which partly inhibits PRMT5, and induces a dependency on residual PRMT5 activity; a dependency that can be pharmacologically exploited. This review describes the MTAP-PRMT5 synthetic lethal axis from molecular biology to clinical translation. First-generation non-selective PRMT5 inhibitors were limited by hematological toxicity and reduced potency in MTA-rich environments. Second-generation MTA-cooperative inhibitors, which overcome these constraints by selectively stabilizing the inactive PRMT5-MTA complex, are characterized by tumor selectivity. Early-phase clinical data for MTA cooperative PRMT5 inhibitors showed encouraging signals of efficacy with manageable safety profiles in early phase trials, establishing clinical proof of concept. Various agents have now entered next steps of clinical development either alone or in combination. In this review we also discuss the biomarker challenges, essential to.

selection, including the limitations of different methods, as well as emerging resistance mechanisms to PRMT5 inhibitors. Molecular testing standardization, pharmacodynamic endpoint integration, and prospective resistance characterization are identified as priorities for next phases of development of PRMT5 inhibition.