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Visualizing DNA Damage Repair Proteins in Patient-Derived Ovarian Cancer Organoids via Immunofluorescence Assays
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DYRK1B Inhibition by AZ191 Sensitizes High-Grade Serous Ovarian Cancer to Niraparib Through Promoting Apoptosis and

Yu Gao1, Yuanyuan Cao2, Junyao Liu2

  • 1Department: of Oncology, First Affiliated Hospital, Dalian Medical University, Dalian 116011, China.

Biomedicines
|May 4, 2026
PubMed

Insights

Combining a DYRK1B inhibitor with Niraparib shows promise for ovarian cancer. This novel approach enhances treatment efficacy in both homologous recombination deficiency (HRD) and proficiency (HRP) patients by increasing DNA damage and inducing ferroptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Ovarian cancer treatment faces challenges with PARP inhibitors, including limited efficacy in homologous recombination proficiency (HRP) patients and acquired resistance in homologous recombination deficiency (HRD) patients.
  • High-grade serous ovarian cancer (HGSOC) requires novel therapeutic strategies to overcome resistance and improve maintenance regimens.
  • DYRK1B (dual-specificity tyrosine-phosphorylation-regulated kinase 1B) has emerged as a potential therapeutic target in various cancers.

Purpose of the Study:

  • To investigate the synergistic effect of a DYRK1B inhibitor (AZ191) combined with a PARP inhibitor (Niraparib) in high-grade serous ovarian cancer (HGSOC).
  • To elucidate the molecular mechanisms underlying the combination therapy's efficacy.
  • To explore the potential of this combination as a novel treatment strategy for both HRD and HRP ovarian cancer patients.

Main Methods:

  • Bioinformatics analysis to assess DYRK1B expression and its prognostic significance in ovarian cancer.
  • In vitro studies using MTT assays to evaluate the therapeutic effects of AZ191 and Niraparib combination on HGSOC cells and organoids.
  • Flow cytometry and Western blot analyses to investigate the synergistic molecular mechanisms, including DNA damage, apoptosis, and ferroptosis pathways (Nrf2/SLC7A11/GPX4 axis).

Main Results:

  • High DYRK1B expression in serous ovarian cancer correlates with poor patient prognosis.
  • The combination of AZ191 and Niraparib demonstrated enhanced therapeutic effects on HGSOC cells and organoids, irrespective of HRD status.
  • Mechanistically, the combination synergistically increased DNA damage and apoptosis, and induced ferroptosis via inhibition of the Nrf2/SLC7A11/GPX4 axis, leading to increased cytotoxicity.

Conclusions:

  • Inhibiting DYRK1B enhances the anti-cancer efficacy of Niraparib in HGSOC.
  • The combination therapy induces cell death through synergistic DNA damage, apoptosis, and ferroptosis.
  • This novel therapeutic strategy targeting DYRK1B may offer a promising approach to improve maintenance therapy for both HRD and HRP ovarian cancer patients.
Keywords:
DYRK1BPARP inhibitorapoptosisferroptosisovarian cancer

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