Abstract 1869: Combining FGTI-2734 and MRTX1133 to suppress ERK-driven resistance in KRAS G12D pancreatic cancer.

Abstract The KRAS G12D-selective inhibitor MRTX1133 marks a significant step forward in targeting mutant KRAS; however, its therapeutic impact is dampened by adaptive resistance driven by ERK pathway reactivation, a process requiring membrane localization of wild-type (WT) RAS. In this study, we introduce a rational approach to circumvent this resistance by using FGTI-2734, a dual inhibitor of farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT-1) that impairs WT RAS and mutant RAS membrane Localization. FGTI-2734 suppresses the ERK rebound elicited by MRTX1133 and acts synergistically with MRTX1133 to inhibit cell growth and trigger apoptosis in KRAS G12D pancreatic cancer cell lines. In patient-derived organoids from 12 individuals with KRAS G12D pancreatic cancer, including organoids originating from both primary and metastatic sites and spanning diverse co-mutation patterns (KRAS, TP53, CDKN2A, SMAD4, RTKs, PI3K/AKT, JAK/STAT, DNA repair/cell-cycle genes, and chromatin modifiers), the FGTI-2734/MRTX1133 combination produced consistent strong synergy. This effect was observed regardless of prior treatment, disease stage, or intrinsic sensitivity or resistance to MRTX1133. In vivo, FGTI-2734 potentiated MRTX1133’s anti-tumor effects, leading to tumor regression in orthotopic patient-derived xenografts established from a KRAS G12D pancreatic cancer patient who progressed after radiation and chemotherapy, as well as in xenografts derived from KRAS G12D human pancreatic cancer cell lines. Importantly, FGTI-2734 treatment prevented MRTX1133-driven ERK reactivation in these KRAS G12D xenograft models. Collectively, these results define a mechanistically grounded combination strategy that neutralizes a key resistance pathway limiting MRTX1133 efficacy, and they highlight a promising therapeutic option for KRAS G12D pancreatic cancers. Citation Format: Deblina Ghosh, Aslamuzzaman Kazi, Hitesh Kumar Kantilal Vasiyani, Vignesh Vudatha, Nicolas Lecomte, Christine A. Iacobuzio-Donahue, Jose G. Trevino, Said M. Sebti. Combining FGTI-2734 and MRTX1133 to suppress ERK-driven resistance in KRAS G12D pancreatic cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1869.