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 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. CRISPR/Cas9 loss-of-function screens implicated co-targeting 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 inhibition disrupted RNA splicing of genes essential for PDAC growth. While PRMT5 and KRAS regulated distinct transcriptomes, they converged on pathways governing cancer cell growth and expression of PDAC-essential genes. These findings provide rationale for combined inhibition of PRMT5 and KRAS in MTAP-deleted/KRAS-mutant PDAC.