Related Experiment Video

Updated: May 21, 2025

Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
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CDK4/6 Inhibitor Can Improve Niraparib Sensitivity and Reverse Acquired Drug Resistance Through Endonuclease G

Tianyu Zhou1, Yahui Jiang1, Xiaoxia Che1

  • 1Department of Obstetrics and Gynecology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

BJOG : an International Journal of Obstetrics and Gynaecology
|April 21, 2025
PubMed
Abstract

Insights

The combination of CDK4/6 inhibitor TQB-3616 and niraparib ZL-2306 shows synergistic effects against BRCA wild-type ovarian cancer. This novel approach may overcome drug resistance and offers a new treatment strategy for refractory ovarian cancer.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Ovarian cancer remains a significant health challenge, particularly BRCA wild-type cases.
  • Drug resistance to PARP inhibitors like niraparib is a major clinical obstacle.
  • Targeting cell cycle pathways alongside DNA repair mechanisms presents a potential therapeutic strategy.

Purpose of the Study:

  • To evaluate the synergistic efficacy of combining a CDK4/6 inhibitor (TQB-3616) with niraparib (ZL-2306) in BRCA wild-type ovarian cancer.
  • To elucidate the underlying mechanisms of this combined therapeutic approach.
  • To assess the potential of this combination in overcoming niraparib resistance.

Main Methods:

  • Generation of a niraparib-resistant ovarian cancer cell line (SKOV3-NR) from the parental SKOV3 cell line.
  • In vitro assessment of combined TQB-3616 and ZL-2306 effects on cell viability, apoptosis, and cell cycle progression.
  • In vivo efficacy studies in a tumor-bearing nude mouse model.
  • Proteomic mass spectrometry to identify mechanisms of action.

Main Results:

  • The combination of TQB-3616 and ZL-2306 demonstrated synergistic inhibition of ovarian cancer cell growth and reversed niraparib resistance in vitro.
  • The combined therapy was effective in suppressing tumor growth in a xenograft mouse model.
  • DNA damage and induction of mitochondrial apoptosis, involving EndoG nuclear translocation, were identified as key mechanisms.

Conclusions:

  • Combined treatment with TQB-3616 and ZL-2306 exhibits synergistic antitumour activity against BRCA wild-type ovarian cancer without increased toxicity.
  • The mechanism involves promoting mitochondrial apoptosis via EndoG nuclear translocation.
  • This combination therapy represents a promising novel strategy for treating refractory ovarian cancer.
Keywords:
CDK4/6 inhibitorPARP inhibitordrug resistanceovarian cancer

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