JPI-547, a Dual Inhibitor of PARP/Tankyrase, Shows Antitumor Activity Against Pancreatic Cancers with Homologous Recombination Repair Deficiency or Wnt-Addiction.

PARP inhibitors have demonstrated antitumor efficacy in solid tumors, including pancreatic ductal adenocarcinoma (PDAC) characterized by homologous recombination deficiency (HRD). The definition of HRD and other potential biomarkers should be further evaluated using PARP inhibitors. JPI-547 is a novel dual inhibitor targeting PARP1/2 and Tankyrase1/2. Herein, we demonstrate the potent antitumor activity of JPI-547 against BRCA2^-/- PDAC cells. JPI-547 outperformed most PARP inhibitors, with a half-maximal inhibitory concentration approximately 10-fold lower than that of olaparib. JPI-547 efficiently trapped PARP1 on the chromatin, disrupted poly-ADP-ribosylation, induced G2/M phase arrest, and triggered apoptosis in PDAC cells. In addition to HRD, we identified Wnt addiction as a predictive factor for JPI-547 activity. PDAC cells reliant on Wnt signaling due to pathogenic RNF43 mutations showed increased susceptibility to JPI-547 without altering homologous recombination repair efficiency. JPI-547 disrupts the Wnt/β-catenin pathway in RNF43-mutated cells and inhibits the oncogenic YAP pathway, highlighting its multifaceted therapeutic potential in PDAC with HRD or Wnt-addiction.