XPO1 inhibition enhances the efficacy and durability of RAS-targeted therapy in preclinical models of KRASG12D mutant pancreatic ductal adenocarcinoma.
KRASG12D-selective and pan-RAS inhibitors have shown promise in pancreatic ductal adenocarcinoma (PDAC), yet adaptive resistance is anticipated to limit durability of response. Exportin 1 (XPO1), a nuclear export protein frequently overexpressed in PDAC, represents a potential vulnerability in KRAS-mutant cancers. We evaluated whether pharmacologic inhibition of XPO1 enhances therapeutic efficacy and durability of KRAS pathway inhibition. KRASG12D inhibitor- and pan-RAS inhibitor-resistant PDAC cellular models were generated and assessed for sensitivity to the second-generation XPO1 inhibitor Eltanexor. Antiproliferative synergistic effects of Eltanexor combined with MRTX1133, Zoldonrasib (RMC9805), or Daraxonrasib (RMC6236) were evaluated in PDAC 2D cultures, 3D spheroids, patient-derived organoids, and tumor-fibroblast co-culture models. Eltanexor sensitized KRAS inhibitor-resistant PDAC cells and synergistically enhanced growth suppression across multiple KRASG12D-mutant models. Combination treatment reduced clonogenic survival, disrupted 3D spheroid integrity, and significantly inhibited viability of patient-derived organoids. The in vivo efficacy of the combination was tested in PDAC cell-derived xenograft/allograft and patient-derived xenograft models. Combining sub-therapeutic doses of Eltanexor with allele-specific inhibitors or pan-RASi resulted in significant tumor regression, prevention of metastatic spread and prolonged survival in vivo. Notably, Eltanexor maintenance therapy suppressed tumor regrowth following RAS inhibitor withdrawal and preserved responsiveness upon re-challenge. Mechanistically, molecular and phosphokinome profiling showed that the combination broadened suppression of MAPK- and mTOR-associated signaling and reduced activity of multiple oncogenic kinases. In conclusion, XPO1 inhibitor Eltanexor enhances the efficacy and durability of KRAS and pan-RAS inhibition in PDAC models. These findings provide a preclinical rationale for clinically evaluating Eltanexor in combination with RAS-targeted therapies to delay or overcome adaptive resistance in KRAS-mutant PDAC.