The potential and challenges of targeting MTAP-negative cancers beyond synthetic lethality.

ABSTRACT: Approximately 15% of cancers exhibit loss of the chromosomal locus 9p21.3 - the genomic location of the tumour suppressor gene CDKN2A and the methionine salvage gene methylthioadenosine phosphorylase (MTAP). A loss of MTAP increases the pool of its substrate methylthioadenosine (MTA), which binds to and inhibits activity of protein arginine methyltransferase 5 (PRMT5). PRMT5 utilises the universal methyl donor S-adenosylmethionine (SAM) to methylate arginine residues of protein substrates and regulate their activity, notably histones to regulate transcription. Recently, targeting PRMT5, or MAT2A that impacts PRMT5 activity by producing SAM, has shown promise as a therapeutic strategy in oncology, generating synthetic lethality in MTAP-negative cancers. However,

SUBMITTER: Bray C 

PROVIDER: S-EPMC10546069 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature