Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy driven predominantly by KRAS mutations, with KRAS G12D present in ~40 % of cases. Although the selective KRAS G12D inhibitor MRTX1133 shows promising activity, monotherapy responses are incomplete and resistance emerges rapidly. In this study, we show that KRAS G12D blockade suppresses homologous-recombination (HR) repair by downregulating BRCA1, RAD51, and RPA32, creating a state of HR deficiency that sensitizes PDAC cells to poly(ADP-ribose) polymerase (PARP) inhibition. Combined MRTX1133 and olaparib treatment produced synergistic cytotoxicity in vitro and durable tumor regression in vivo, even in MRTX1133-resistant models, and remodeled the tumor immune microenvironment with enhanced CD8 + T-cell infiltration. These findings demonstrate that co-targeting KRAS G12D and PARP exploits an induced DNA-repair vulnerability to achieve synthetic lethality and immune activation in KRAS G12D -driven PDAC. KRASG12D -mutant pancreatic tumors are aggressive and resist therapy. Here the authors show that inhibiting KRASG12D weakens tumor DNA repair, sensitizing them to the PARP inhibitor olaparib, even in KRASG12D inhibitor-resistant tumors.