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Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
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CDCA5 knockdown potentiates olaparib sensitivity in BRCA1-mutated ovarian cancer through autophagy activation

Wenzong Wu1, Huan Wu2, Yuqing Song3

  • 1Department of Clinical Medicine, Bengbu Medical University, Bengbu, 233000, Anhui, China.

Discover Oncology
|September 30, 2025
PubMed
Abstract

Insights

CDCA5 silencing combined with olaparib enhances treatment for BRCA1-mutated ovarian cancer by promoting autophagy and DNA damage. This combination overcomes resistance to PARP inhibitors, improving patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • BRCA1-mutated ovarian cancer presents poor prognosis and resistance to conventional treatments.
  • PARP inhibitors like olaparib show promise but acquired resistance remains a challenge.
  • Investigating novel therapeutic strategies is crucial for improving treatment efficacy.

Purpose of the Study:

  • To evaluate the therapeutic potential of combining CDCA5 silencing with olaparib in BRCA1-mutated ovarian cancer.
  • To elucidate the underlying mechanisms of this combination therapy.
  • To explore a novel approach for overcoming PARP inhibitor resistance.

Main Methods:

  • Utilized BRCA1-mutated ovarian cancer cell lines and xenograft models.
  • Performed CDCA5 knockdown alone and in combination with olaparib.
  • Conducted functional assays including CCK-8, immunofluorescence, TEM, and western blot to assess proliferation, autophagy, DNA damage, and PI3K/AKT/mTOR signaling.

Main Results:

  • CDCA5 knockdown inhibited proliferation, induced autophagy, and caused DNA damage in cancer cells.
  • The combination of CDCA5 knockdown and olaparib synergistically enhanced these effects, leading to significant in vivo tumor growth inhibition.
  • Mechanistically, the combination suppressed the PI3K/AKT/mTOR pathway, promoting autophagy and DNA damage, which were reversed by PI3K/AKT/mTOR activation.

Conclusions:

  • CDCA5 knockdown potentiates the anticancer effects of olaparib in BRCA1-mutated ovarian cancer.
  • The combination therapy promotes autophagy and exacerbates DNA damage through the PI3K/AKT/mTOR pathway.
  • This study presents a novel therapeutic strategy to overcome PARP inhibitor resistance and improve treatment outcomes for BRCA1-mutated ovarian cancer.
Keywords:
ARP inhibitorsAutophagyBRCA1-mutated ovarian cancerCDCA5OlaparibPI3K/AKT/mTOR pathway

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