Potent antitumor activity of the KRAS ^G12D inhibitor MRTX1133 in pancreatic cancer: Augmenting the nanoparticle-paclitaxel chemotherapy response.

e16358 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with an extremely poor prognosis. The combination of nab-paclitaxel and gemcitabine (NPT-GEM) is the current standard treatment for advanced and metastatic PDAC, providing a median survival of approximately 8.5 months. Genetic studies have identified KRAS, TP53, p16/CDKN2A , and SMAD4 as the most frequently mutated genes in PDAC, with KRAS mutations present in over 90% of cases and playing a pivotal role in tumorigenesis. The predominant KRAS mutation subtypes in PDAC are G12D (~49%), G12V (~30%), and G12R (~12%). Recent advances in direct KRAS inhibitors offer promising new opportunities to improve PDAC therapy. MRTX1133, a novel KRAS inhibitor, specifically targets the KRAS G12D mutation in both active and inactive states, selectively inhibiting KRAS G12D -mutant tumor cells while sparing wild-type KRAS (KRAS wt ), underscoring its significant therapeutic potential for PDAC. Methods: In vitro proliferation assays were performed on PDAC epithelial cells harboring KRAS G12D mutations, KRAS G12C mutations, or KRAS wt 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 bearing AsPC-1 subcutaneous xenografts. Results: MRTX1133 and NPT-Gem treatment demonstrated dose-dependent inhibition of in vitro proliferation in KRAS G12D -mutant PDAC cell lines (AsPC-1, HPAF-II, SW-1990). A synergistic effect was observed with the combination therapy. MRTX1133 alone had minimal effects on KRAS G12C -mutant Mia PaCa-2 cells and KRAS wt BxPC-3 cells. Immunoblot analysis of KRAS G12D -mutant cells (AsPC-1 and HPAF-II) showed that MRTX1133 treatment reduced phosphorylation of ERK, AKT, S6, MEK, RAF, while increasing the expression of apoptosis marker proteins, cleaved-PARP-1 and cleaved-caspase-3. In vivo tumor growth inhibition studies revealed significant delays in tumor growth with MRTX1133 and NPT-GEM, with their combination demonstrating synergistic effects. Compared to the control (average net tumor growth: 327 mm 3 ), NPT-GEM reduced growth to 129 mm 3 , MRTX1133 reduced it to 56 mm 3 , and the combination resulted in tumor regression (-4 mm 3 ). Tumor weight findings aligned with these results. Importantly, no significant body weight changes were observed in treated mice, indicating no discernable toxicity associated with MRTX1133, NPT-GEM, or their combination. Conclusions: The significant antitumor efficacy of MRTX1133, especially when combined with the nanoparticle-paclitaxel chemotherapy regimen, holds substantial promise for enhancing the clinical management of patients with KRAS G12D -mutant PDAC.