The potential and challenges of targeting MTAP-negative cancers beyond synthetic lethality
Approximately 15% of cancers show a loss at the chromosomal locus 9p21.3, which contains the tumor suppressor gene CDKN2A and the methionine salvage gene methylthioadenosine phosphorylase (MTAP). The loss of MTAP leads to an accumulation of its substrate, methylthioadenosine (MTA), which binds to and inhibits the activity of protein arginine methyltransferase 5 (PRMT5). PRMT5 uses the universal methyl donor S-adenosylmethionine (SAM) to methylate arginine residues on protein substrates, including histones, thus regulating transcription.
Recently, targeting PRMT5 and MAT2A, which produces SAM and influences PRMT5 activity, has emerged as a promising therapeutic strategy in oncology, particularly in inducing synthetic lethality in MTAP-negative cancers. However, the clinical development of inhibitors for PRMT5 and MAT2A has faced challenges, underscoring the need for a deeper understanding of the downstream mediators involved in their effects.
In this article, we discuss the rationale and methodologies for targeting the MAT2A/PRMT5 axis in cancer therapy. We evaluate current limitations in understanding how MAT2A/PRMT5 inhibitors work and identify challenges that need to be addressed to fully realize the potential of these drugs. Additionally, we review existing literature on the downstream effectors of PRMT5 activity that could influence sensitivity to MAT2A/PRMT5 inhibition, AGI-24512 providing a basis for novel combination therapies that may not depend on synthetic lethality associated with MTAP loss.