Abstract 3786: Combination of MTA-cooperative PRMT5 inhibitor BMS-986504 and KRAS inhibitors for the treatment of <i>MTAP</i>-deleted <i>KRAS</i>-mutant pancreatic cancer

Abstract Protein arginine methyltransferase 5 (PRMT5) is a synthetic lethal target in cancers harboring genomic deletions of the MTAP gene, which encodes the enzyme methylthioadenosine phosphorylase. Approximately one in four pancreatic ductal adenocarcinoma (PDAC) cases harbor homozygous deletion of the MTAP gene (MTAP-del), providing a promising novel targeted therapy for PDAC. The methylthioadenosine (MTA)-cooperative PRMT5 inhibitor BMS-986504 (previously known as MRTX1719) leverages the elevated MTA levels present in MTAP-del tumors to selectively block PRMT5 function in cancer but not normal cells and tissues. BMS-986504 demonstrated clinical activity in MTAP-del cancers without the dose-limiting hematological toxicity associated with previous first-generation PRMT5 inhibitors, however the utility of this approach has not been thoroughly investigated in PDAC. Here, we demonstrated that BMS-986504 suppressed PRMT5 function and cell growth in MTAP-del PDAC cells in vitro and in established cell line- and patient-derived xenograft mouse models. Furthermore, CRISPR/Cas9 screens were performed using the MTAP-del, KRAS-mutant MIA PaCa-2 cell line in vitro and in vivo to identify genes that modulated sensitivity to BMS-986504. We identified KRAS as one of the top depleted target genes in both screens (in the top 50 in vitro and the top 20 in vivo). We validated co-targeting KRAS as a combination strategy and found that combined small molecule inhibition of PRMT5 and G12C/D-mutant KRAS (using adagrasib and MRTX1133, respectively) effectively suppressed MTAP-del PDAC growth in vitro and in vivo. We also performed RNA-Seq analysis and determined that PRMT5 inhibition disrupts RNA splicing of genes that are essential for PDAC growth. Further, we determined that, while PRMT5 and KRAS regulate distinct transcriptomes, they converge on common pathways governing cancer cell growth and combined inhibition of PRMT5 and KRAS caused marked downregulation of PDAC-essential genes. These findings provide a rationale for combined inhibition of PRMT5 and KRAS to maximize targeted therapies for MTAP-del and KRAS-mutant biomarker-positive PDAC. Citation Format: Kristina Drizyte-Miller, Lars D. Engstrom, Jeffrey A. Klomp, Clint A. Stalnecker, Laura Waters, Andrew Calinisan, Ryan Robb, Khalilah E. Taylor, Mallory K. Roach, Addison G. Stamey, Seamus Degan, Wen-Hsuan Chang, Xousaen M. Helu, David Nguyen, Laura D. Hover, Elisa Baldelli, Mariaelena Pierobon, Emanuel F. Petricoin, Kirsten L. Bryant, David M. Briere, James G. Christensen, Jill Hallin, Adrienne D. Cox, Peter Olson, Channing J. Der. Combination of MTA-cooperative PRMT5 inhibitor BMS-986504 and KRAS inhibitors for the treatment of MTAP-deleted KRAS-mutant pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3786.