Combination of the MTA-Cooperative PRMT5 Inhibitor BMS-986504 and KRAS Inhibitors is an Effective Treatment Strategy for MTAP-Deleted KRAS-Mutant Pancreatic Cancer.

Protein arginine methyltransferase 5 (PRMT5) is a synthetic lethal target in MTAP-deleted (MTAP-del) cancers. The MTA-cooperative PRMT5 inhibitor BMS-986504 exhibited potent and selective anti-tumor activity in MTAP-del preclinical models and demonstrated activity in MTAP-del patients without the toxicity associated with previous PRMT5 inhibitors. Here, we focused on pancreatic ductal adenocarcinoma (PDAC), ~22% of which are MTAP-del, and demonstrated that BMS-986504 suppressed PRMT5 function and cell growth in MTAP-del cells and xenograft models.