Abstract 3319: The MTA-cooperative PRMT5 inhibitor, MRTX1719, demonstrates increased anti-tumor activity in combination with KRAS mutant-selective inhibitors in MTAP del,KRAS-mutant cancers

Abstract MRTX1719 is an MTA-cooperative PRMT5 inhibitor that leverages the increased concentration of the metabolite MTA in cancer cells harboring a homozygous deletion of the MTAP gene (MTAP del) under investigation in clincial trials. MRTX1719 preferentially binds to the PRMT5•MTA complex to selectively inhibit PRMT5, an essential gene for all cells, in MTAP del cancer cells while sparing PRMT5 activity in normal MTAP-wildtype cells. MTAP del occurs in ~10% of all cancers, and these patients exhibit remarkably poor survival. Among pancreatic cancer, MTAP del occurs in ~ 25% of patients and of these ~30% have co-occurring KRAS G12D mutations. In addition, ~15% of lung adenocarcinoma patients harbor MTAP del and of these ~13% harbor KRAS G12C. While recently approved KRAS G12C mutant selective inhibitors demonstrate anti-tumor activity, strategies to address drug resistance and maximize clinical benefit are warranted. Combination of MRTX1719 with adagrasib or the KRAS G12D inhibitor MRTX1133 in CDX models harboring both a KRAS mutation (G12C or G12D) and homozygous MTAP deletion resulted in increased anti-tumor activity compared to either single agent. This includes the pancreatic KP4 model in which initial tumor regression in response to single agent MRTX1133 was observed, followed by adaptative resistance and tumor progression with monotherapy while co-administration with MRTX1719 continued to result in marked tumor regression. Mechanistically, combination treated animals demonstrated strong inhibition of both PRMT5 and RAS pathway signaling and combinatorial targeting of these pathways converged on enhanced inhibition of RB-1 phosphorylation. We also characterized this combination treatment in the context of resistance to KRAS selective inhibitors or MRTX1719 to evaluate the benefit of combination over sequential treatment. Finally, an NF1 mutant, MTAP del malignant peripheral nerve sheath tumor (MPNST) PDX model was treated with MRTX1719, the SOS1 inhibitor MRTX0902, or the combination, and a similar increase in anti-tumor activity was observed in the combination treatment compared to either monotherapy alone. These results suggest that the combination of an MTA-cooperative PRMT5 inhibitor with a KRAS mutant selective or KRAS pathway inhibitor may lead to deeper and more durable responses in MTAP del cancer patients with co-alterations in the KRAS pathway. Citation Format: Laura Waters, Ruth Aranda, Xousaen Helu, Laura Vegar, Krystal Moya, Andrew Calinisan, Allan Hebbert, Jill Hallin, Darin Vanderpool, David M. Briere, James G. Christensen, Peter A. Olson, Lars D. Engstrom. The MTA-cooperative PRMT5 inhibitor, MRTX1719, demonstrates increased anti-tumor activity in combination with KRAS mutant-selective inhibitors in MTAP del, KRAS-mutant cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3319.