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JPI-547, a Dual Inhibitor of PARP/Tankyrase, Shows Antitumor Activity Against Pancreatic Cancers with Homologous

Kyoung-Seok Oh1, Ah-Rong Nam1, Ju-Hee Bang1

  • 1Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.

International Journal of Biological Sciences
|September 17, 2025
PubMed

Insights

A novel dual inhibitor, JPI-547, shows potent antitumor activity in pancreatic ductal adenocarcinoma (PDAC) with homologous recombination deficiency (HRD) or Wnt-addiction. It effectively targets PARP1/2 and Tankyrase1/2, outperforming other PARP inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • PARP inhibitors demonstrate antitumor efficacy in solid tumors like pancreatic ductal adenocarcinoma (PDAC).
  • Homologous recombination deficiency (HRD) is a key characteristic in some PDAC cases, influencing treatment response.
  • Evaluating biomarkers and novel inhibitors is crucial for advancing PDAC therapy.

Purpose of the Study:

  • To evaluate the antitumor activity of JPI-547, a novel dual PARP1/2 and Tankyrase1/2 inhibitor, in PDAC.
  • To identify predictive biomarkers for JPI-547 response beyond HRD.
  • To elucidate the mechanisms of action of JPI-547 in PDAC cells.

Main Methods:

  • In vitro assessment of JPI-547 efficacy in BRCA2-/- PDAC cells.
  • Comparison of JPI-547's half-maximal inhibitory concentration (IC50) with olaparib.
  • Analysis of JPI-547's effects on PARP1 chromatin trapping, poly-ADP-ribosylation, cell cycle, and apoptosis.
  • Investigation of Wnt signaling pathway dependency and RNF43 mutations as predictive factors.

Main Results:

  • JPI-547 exhibited potent antitumor activity against BRCA2-/- PDAC cells, with an IC50 approximately 10-fold lower than olaparib.
  • JPI-547 effectively trapped PARP1, disrupted poly-ADP-ribosylation, induced G2/M arrest, and triggered apoptosis.
  • Wnt addiction, driven by RNF43 mutations, was identified as a predictive biomarker for JPI-547 sensitivity.
  • JPI-547 inhibited Wnt/β-catenin and YAP pathways in RNF43-mutated PDAC cells.

Conclusions:

  • JPI-547 demonstrates significant preclinical efficacy in PDAC, particularly in tumors with HRD or Wnt-addiction.
  • The dual inhibition of PARP and Tankyrase by JPI-547 offers a multifaceted therapeutic approach.
  • RNF43 mutations and Wnt pathway dependency represent novel predictive markers for JPI-547 treatment in PDAC.
Keywords:
PARPPARP inhibitorRNF43TankyraseWnt/B-catenin.homologous recombination deficiency

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