OBJECTIVES: Synthetic lethality (SL), the simultaneous occurrence of two genetic events leading to cell death has been successful in the clinical development of PARP inhibitors for BRCA-mutated cancers. Targeting protein arginine methyltransferase 5 (PRMT5) in oncology shows promise by leveraging its role in S-adenosylmethionine production. This strategy exploits SL in methyl thioadenosine phosphorylase (MTAP)-lacking cancers, crucial for the methionine salvage pathway. This scoping review focused on existing studies and technologies reported for PRMT5 inhibition in MTAP-deleted cancers as a therapeutic strategy in oncology.

METHODS: We conducted a literature search using PubMed and Google Scholar via AI powered tool – MaiA. We included clinical trials, observational studies, reviews, systematic literature reviews, and meta-analyses published within the last 10 years (until April 30, 2024) related to PRMT5 inhibitors in MTAP-deleted cancer cells. Data charting elements included in-vitro cellular information (IC50, substrate binding capacity, cancer cell line, cytotoxicity, pharmacokinetic profile), clinical trial information (therapeutic molecule, company, tumour type, route of administration, trial phase, NCT number) and conclusion.

RESULTS: This scoping review analysed 560 studies, selecting 100 preclinical studies and 25 clinical trials for final evaluation. In the preclinical studies, various chemotherapeutic combinations with PRMT5 inhibitors were investigated in MTAP-deleted cancers. Notably, six oral PRMT5 inhibitors—MRTX1719, AG-270, AMI, LLY-238, HLCL-61, and EPZ015666 demonstrated significant antitumor activity in MTAP-deleted tumours in mouse xenograft models. Despite these promising results, over 75% of preclinically validated PRMT5 inhibitors have not advanced to clinical trials. Among the 25 clinical trials, two PRMT5 inhibitors, AMG193 (NCT05975073) and TNG908 (NCT05275478) are currently in Phase 1/2 trials targeting MTAP-null solid tumours.

CONCLUSIONS: There is compelling evidence supporting the initial stages of drug development aimed at PRMT5 in MTAP-deleted cancers. Additional research is required to clarify molecular mechanisms and improve the clinical viability of this SL combination.