FGTI-2734 prevents ERK-mediated resistance and enhances MRTX1133 efficacy in KRAS G12D pancreatic cancer.

The KRAS G12D inhibitor MRTX1133 represents a major advance in targeting oncogenic KRAS, but adaptive resistance driven by ERK reactivation, dependent on wild-type (WT) RAS membrane localization, limits its efficacy. Here, we identify a rational strategy to overcome this resistance mechanism using FGTI-2734, a dual farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT-1) inhibitor that disrupts WT RAS membrane localization. FGTI-2734 blocks MRTX1133-induced ERK feedback reactivation and synergizes with MRTX1133 to inhibit proliferation and induce apoptosis in KRAS G12D pancreatic cancer cell lines. Across organoids derived from 12 patients with KRAS G12D pancreatic cancer, including those with primary and metastatic tumors with diverse genetic alterations (KRAS, TP53, CDKN2A, SMAD4, RTKs, PI3K/AKT, JAK/STAT, DNA repair/cell cycle, and chromatin modifiers), the MRTX1133/FGTI-2734 combination produced robust synergy regardless of tumor stage, treatment status, or MRTX1133 resistance. In vivo, FGTI-2734 enhanced MRTX1133 anti-tumor activity, driving significant tumor regression in orthotopic patient-derived xenografts from a KRAS G12D pancreatic cancer patient who relapsed after radiation and chemotherapy, as well as KRAS G12D human pancreatic tumor cell xenografts. Notably, treatment of mice with FGTI-2734 inhibited MRTX1133-induced ERK reactivation in KRAS G12D pancreatic cancer xenografts. These findings establish a combination strategy that overcomes a significant mechanism of resistance to MRTX1133 and offer a potential treatment option for pancreatic cancers, including those refractory to current therapies.