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

ABSTRACT: 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 antitumor activity in MTAP-del preclinical models and demonstrated activity in MTAP-del patients without the toxicity associated with previous PRMT5 inhibitors. In this study, 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. CRISPR/Cas9 loss-of-function screens implicated cotargeting KRAS as a combination strategy. Concurrent inhibition of PRMT5 and KRASG12C/D enhanced and prolonged suppression of PDAC growth. RNA sequencing analysis revealed that PRMT5 inhib

SUBMITTER: Drizyte-Miller K 

PROVIDER: S-EPMC12717533 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature