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 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 inhibition disrupted RNA splicing of genes essential for PDAC growth. Although 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-del/KRAS-mutant PDAC. SIGNIFICANCE: MTAP deletion and mutational activation of KRAS create therapeutic vulnerabilities for MTA-cooperative PRMT5 and mutant-selective KRAS inhibitors, respectively, providing the rationale for their combination therapy for MTAP-deleted, KRAS-mutant pancreatic cancer. See related article by Knoll et al., p. 3518.