Abstract 5640: The KRASG12Dinhibitor MRTX1133 demonstrates significant antitumor activity and enhances nanoparticle-paclitaxel chemotherapy outcomes in pancreatic cancer

Abstract Objective: Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with an extremely grim prognosis. The combination of nab-paclitaxel and gemcitabine (NPT-GEM) represents the standard treatment for advanced and metastatic PDAC, yielding a median survival of approximately 8.5 months. Genetic studies have identified KRAS, TP53, p16/CDKN2A, and SMAD4 as the most commonly mutated genes in PDAC, with KRAS mutations occurring in over 90% of cases, and playing a central role in tumorigenesis. The KRAS-mutation subtypes most common in PDAC are G12D (∼49%), G12V (∼30%), and G12R (∼12%). Recent advances in direct KRAS inhibitors provide new opportunities for improving PDAC therapy. MRTX1133, a novel KRAS inhibitor, specifically targets the KRASG12D mutation in both active and inactive states, selectively inhibiting KRASG12D-mutant tumor cells while sparing wild-type KRAS, highlighting its significant therapeutic potential for PDAC. Methods: In vitro proliferation assays were performed on PDAC epithelial cells harboring KRASG12D-mutations, KRASG12C-mutations, or KRASwt using the colorimetric WST-1 method. Protein expression levels were assessed via Immunoblot analysis. Tumor growth studies were conducted using 4-6-week-old female NOD/SCID mice with AsPC-1 subcutaneous xenografts. Results: In vitro assays demonstrated dose-dependent inhibition of proliferation in KRASG12D-mutant PDAC cell lines (AsPC-1, HPAF-II, SW-1990) treated with MRTX1133 and NPT-GEM. A synergistic effect was observed with the combination therapy. MRTX1133 alone had minimal effects on KRASG12C-mutant Mia PaCa-2 cells and KRASwt BxPC-3 cells. Immunoblot analysis of KRASG12D-mutant cells (AsPC-1 and HPAF-II) revealed that MRTX1133 treatment reduced phosphorylation of ERK, AKT, S6, MEK, RAF, while increasing apoptosis marker proteins cleaved-PARP-1 and cleaved-caspase-3. In vivo tumor growth inhibition studies exhibited significant delays in tumor growth with MRTX1133 and NPT-GEM, with their combination showing synergistic effects. Compared to the control (average net tumor growth: 327 mm3), NPT-GEM reduced growth to 129 mm3, MRTX1133 reduced it to 56 mm3 and the combination resulted in tumor regression (-4 mm3). Tumor weight findings corroborated these results. Importantly, no body weight changes were observed in treated mice, indicating no discernable toxicity associated with MRTX1133, NPT-GEM, or their combination. Conclusion: These findings highlight the significant therapeutic potential of MRTX1133, particularly in combination with standard chemotherapy, for the clinical management of KRASG12D-mutant PDAC patients. Citation Format: Mitchel Ramos, Nicola Grimaldi, Sazzad Hassan, Urs von Holzen, Niranjan Awasthi. The KRASG12Dinhibitor MRTX1133 demonstrates significant antitumor activity and enhances nanoparticle-paclitaxel chemotherapy outcomes in 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 5640.