Combination of PARP and KRAS(G12D) inhibitors enhances therapeutic efficacy by exploiting vulnerabilities in PDAC.

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.