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Dual PARP/Tankyrase Inhibition Enhances Antitumor Efficacy in PTEN-Deficient Endometrial Cancer

Sung Wan Kang1,2,3, Hyerim Eum1,2, Ji-Young Lee1,2

  • 1Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Journal of Cellular and Molecular Medicine
|June 13, 2026
PubMed

Insights

Dual PARP/tankyrase (TNKS) inhibition with JPI-547 shows potent antitumor activity in PTEN-deficient endometrial cancer (EC). This strategy disrupts DNA repair and Wnt signaling, offering a promising therapeutic approach for EC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Endometrial cancer (EC) incidence is rising, necessitating novel therapies.
  • PTEN loss in EC impairs DNA repair, suggesting sensitivity to PARP inhibitors, but resistance limits efficacy.
  • Current treatments for PTEN-deficient EC are limited, highlighting the need for new strategies.

Purpose of the Study:

  • To investigate the efficacy of dual PARP/tankyrase (TNKS) inhibition using JPI-547 in PTEN-deficient endometrial cancer.
  • To explore the mechanisms underlying JPI-547's antitumor activity, including its effects on DNA repair and Wnt signaling.
  • To evaluate the potential of dual PARP/TNKS inhibition as a therapeutic strategy for PTEN-deficient EC.

Main Methods:

  • In vitro experiments using PTEN-deficient Ishikawa cells treated with JPI-547, olaparib, and XAV-939.
  • Assessment of cell survival, DNA double-strand breaks, RAD51 suppression, non-homologous end joining modulation, and Wnt/β-catenin signaling.
  • PTEN knockdown experiments to evaluate enhanced vulnerability to combined targeting.

Main Results:

  • JPI-547 demonstrated potent antitumor activity in PTEN-deficient Ishikawa tumors.
  • Combined treatment with JPI-547 and XAV-939 induced synergistic cytotoxicity and elevated DNA double-strand breaks.
  • Dual PARP/TNKS inhibition modulated non-homologous end joining and attenuated Wnt/β-catenin signaling in a PTEN-dependent manner.
  • PTEN knockdown enhanced sensitivity to combined targeting, indicating PTEN's role in resistance.

Conclusions:

  • JPI-547, a dual PARP/TNKS inhibitor, shows significant antitumor efficacy in PTEN-deficient EC.
  • The drug disrupts DNA repair pathways and Wnt signaling, overcoming resistance mechanisms.
  • Dual PARP/TNKS inhibition represents a promising therapeutic strategy for PTEN-deficient EC, warranting further clinical investigation.
Keywords:
DNA repair pathwayPARP inhibitorPTENendometrial cancertankyrase

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