Synthetic lethality refers to a phenomenon where the simultaneous inactivation of two genes leads to cell death, whereas the disruption of either gene alone does not affect cell survival. Synthetic lethality has emerged as a significant topic in the field of targeted cancer therapy, with certain drugs based on this concept exhibiting promising outcomes in clinical trials.

Protein arginine methyltransferase 5 (PRMT5) has been identified as a synthetic lethal target in cancers with homozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene. PRMT5 is essential for maintaining cellular homeostasis by regulating a variety of processes, including gene transcription, ribosomal biogenesis, mRNA splicing, protein translation, DNA damage response, and immune function. Upregulation of PRMT5 has been associated with poor prognostic outcomes of patients in different cancers, such as lung cancer and glioblastoma multiforme (GBM), highlighting its potential as a therapeutic target.

MTAP plays a key role in the methionine salvage pathway, and its loss results in the accumulation of methylthioadenosine (MTA), which partially inhibits PRMT5 activity. In MTAP-deficient tumor cells, PRMT5 expression and activity become essential for cell growth, making PRMT5 an attractive synthetic lethality target for treating these cancers.

MTAP homozygous deletions occur in 10-15% of human cancers, with higher frequencies observed in various types, including non-small cell lung cancer (NSCLC), mesothelioma, pancreatic cancer, glioblastoma, head and neck cancer, esophageal cancer, and bladder cancer.