Combination strategy targeting protein methylation may improve PARP inhibitor activity

Inherited mutations in BRCA genes cause defects in DNA damage repair pathways. Targeted therapy with PARP inhibitors – which block a DNA repair protein – is known to extend progression-free survival in patients with BRCA-mutant cancers, but many patients eventually develop resistance and have poor overall survival, underscoring a need to identify combination strategies that improve outcomes. Protein arginine methyltransferases (PRMTs), which regulate gene transcription and RNA splicing, are involved in many cancer-associated processes, leading Nidhi Sahni, Ph.D., and colleagues to investigate PRMTs as potential therapeutic targets. Using targeted proteomics on cancer cell lines treated with PRMT inhibitors, the researchers discovered the key DNA replication stress response protein ATR also was suppressed. By combining PRMT and PARP inhibitors, they found that PRMT5 blockade preferentially suppressed ATR in cancer cells. Both in vitro and in vivostudies highlighted PRMT5 inhibition as a well-tolerated approach that merits further evaluation to improve treatment responses in patients given PARP inhibitors.