Strong durable tumor regressions with the KRAS G12D ON/OFF inhibitor VS-7375 in combination with PRMT5 inhibition in MTAP-deleted/KRAS G12D -mutant pancreatic cancer

Clinical evaluation of RAS inhibitors has shown promising efficacy in KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). However, limitations due to intrinsic and acquired resistance underscore the need for rational combination strategies. We recently showed that treatment with the MTA-cooperative PRMT5 inhibitor BMS-986504 selectively inhibited the growth of MTAP-deleted/KRAS-mutant PDAC, and that concurrent PRMT5i treatment enhanced the efficacy of mutant-selective and pan-RAS inhibitors (Drizyte-Miller et al, Cancer Res, 2025). Our findings support PRMT5i as an orthogonal combination strategy to overcome resistance to RAS inhibitors. To extend these findings, we explored the combination of the KRAS G12D -selective ON/OFF-state inhibitor VS-7375/GFH375 (G12Di) with the PRMT5 inhibitor BMS-986504 (PRMT5i) in MTAP-deleted/KRAS G12D -mutant PDAC. In PANC-1 cells, the combination of G12Di + PRMT5i suppressed pERK and pS6 more than either agent alone. In KP4 xenografts, combination with PRMT5i extended the duration of tumor regression induced by G12Di. To determine whether mechanisms of resistance to G12Di and PRMT5i were overlapping, we established PDAC cell models of resistance to PRMT5i, G12Di, or the pan-RAS inhibitor RMC-6236 (RASi). We cultured drug-sensitive KRAS G12D -mutant pancreatic cancer cell lines continuously in the presence of PRMT5i, G12Di, or RASi until resistant subpopulations emerged. Cells resistant to PRMT5i retained sensitivity to G12Di/RASi and vice versa. Thus, consistent with our determination that PRMT5 and KRAS regulate distinct molecular and cellular processes, resistance to each agent likely also involves distinct mechanisms. These data support PRMT5i as a therapeutic approach for patients who relapse on RAS-targeted therapy alone or in combination with RAS inhibitor therapies. Unexpectedly, PRMT5i-resistant cells retained PRMT5 expression yet exhibited a near-complete loss of symmetric dimethylation of arginine (SDMA), the catalytic product of PRMT5, and also lost sensitivity to SAM-selective PRMT5 inhibitors. Further, we found no significant increase in asymmetric dimethylation of arginine (ADMA), catalyzed by the type I methyltransferase PRMT1. Thus, PRMT5i-resistant cells are functionally independent of both PRMT5 and PRMT1. Signaling analyses identified elevated MYC levels as one possible basis of PRMT5i resistance. Ongoing studies to further elucidate PRMT5i resistance mechanisms include global profiling of the transcriptomes and methylomes of sensitive versus resistant cells. Our findings support the therapeutic potential of the combination of VS-7375 with BMS-986504 for KRAS G12D -mutant PDAC that additionally harbor deletion of MTAP. Our demonstration of distinct resistance trajectories to RAS and PRMT5 inhibition further supports this concept.