PARP inhibitor and PRMT5 inhibitor synergy is independent of BRCA1/2 and MTAP status in breast cancer cells

PARP inhibitors have been approved for treating a subset of breast cancer patients harboring BRCA1/2 mutations. However, TNBC patients with wildtype BRCA1/2 have limited targeted therapeutic options. Dysregulation of protein arginine methyltransferase 5 (PRMT5) has been implicated in the progression of various cancers, including breast cancer. This study investigates the effects of two classes of PRMT5 inhibitors, GSK3326595 and TNG908, on breast cancer cell lines with different BRCA1/2 statuses to evaluate their therapeutic potential and synergy with PARP inhibitors. A panel of seven breast cancer cell lines was treated with PRMT5 and PARP inhibitors, followed by cell viability measurements using an MTT assay. Drug interactions were analyzed using the Loewe method on the Combenefit Software. Additionally, RT-qPCR was conducted to measure the expression of known DNA damage response genes. Synergy was observed in all cell lines, with BRCA1/2 wildtype cell lines displaying higher synergy scores than BRCA1/2 mutant lines, while the synergy was independent of MTAP status. Mechanistically, PRMT5 inhibition did not alter the early gene expression of known DNA damage response genes as measured by RT-qPCR. Notably, short-term PRMT5 inhibition was sufficient to sensitize an isogenic pair of ovarian cancer cells to subsequent PARP inhibition. These findings highlight the potential of combining PRMT5 inhibitors with PARP inhibitors in a wide range of cancers beyond BRCA1/2 and MTAP mutants. Further investigation is warranted to elucidate the underlying mechanisms of sensitization and the timing of cellular responses to PRMT5 inhibition.