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Background <p>BRCA1-mutated ovarian cancer poses substantial therapeutic hurdles due to its poor prognosis and resistance to traditional therapies. Although acquired resistance is still a significant obstacle, PARP inhibitors, e.g., olaparib, have demonstrated promise in prolonging progression-free survival (PFS) in these individuals. The therapeutic potential of CDCA5 silencing in conjunction with olaparib to improve treatment effectiveness for ovarian cancer with a BRCA1 mutation is examined in this study.</p> Methods <p>Using BRCA1-mutated ovarian cancer cell lines (UWB1.289 and SNU251) and xenograft models, we analyzed the effects of CDCA5 knockdown alone or combined with olaparib. Functional assays (CCK-8, immunofluorescence, TEM, western blot) evaluated proliferation, autophagy, DNA damage, and PI3K/AKT/mTOR signaling.</p> Results <p>CDCA5 knockdown inhibited proliferation, activated autophagy, and induced DNA damage in BRCA1-mutated cells. Moreover, combination with olaparib synergistically enhanced these effects, with significant tumor growth inhibition in vivo. Mechanistically, the combination suppressed the PI3K/AKT/mTOR pathway, promoting autophagy and exacerbating DNA damage. Pharmacological activation of PI3K/AKT/mTOR reversed these antitumor effects.</p> Conclusions <p>The anticancer effects of olaparib are enhanced by CDCA5 knockdown, which also promotes autophagy and exacerbates DNA damage via the PI3K/AKT/mTOR pathway. These findings provide a novel therapeutic approach for treating BRCA1-mutated ovarian cancer that overcomes PARP inhibitor resistance and enhances treatment results.</p>

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CDCA5 knockdown potentiates olaparib sensitivity in BRCA1-mutated ovarian cancer through autophagy activation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年9月30日

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  • Wenzong Wu,
  • Huan Wu,
  • Yuqing Song,
  • LiuJun Wu,
  • Jiajia Chen,
  • Minsheng Zhu,
  • Xinchun Wu,
  • Jiawei Wang,
  • Qingsong Zhang

摘要

Background

BRCA1-mutated ovarian cancer poses substantial therapeutic hurdles due to its poor prognosis and resistance to traditional therapies. Although acquired resistance is still a significant obstacle, PARP inhibitors, e.g., olaparib, have demonstrated promise in prolonging progression-free survival (PFS) in these individuals. The therapeutic potential of CDCA5 silencing in conjunction with olaparib to improve treatment effectiveness for ovarian cancer with a BRCA1 mutation is examined in this study.

Methods

Using BRCA1-mutated ovarian cancer cell lines (UWB1.289 and SNU251) and xenograft models, we analyzed the effects of CDCA5 knockdown alone or combined with olaparib. Functional assays (CCK-8, immunofluorescence, TEM, western blot) evaluated proliferation, autophagy, DNA damage, and PI3K/AKT/mTOR signaling.

Results

CDCA5 knockdown inhibited proliferation, activated autophagy, and induced DNA damage in BRCA1-mutated cells. Moreover, combination with olaparib synergistically enhanced these effects, with significant tumor growth inhibition in vivo. Mechanistically, the combination suppressed the PI3K/AKT/mTOR pathway, promoting autophagy and exacerbating DNA damage. Pharmacological activation of PI3K/AKT/mTOR reversed these antitumor effects.

Conclusions

The anticancer effects of olaparib are enhanced by CDCA5 knockdown, which also promotes autophagy and exacerbates DNA damage via the PI3K/AKT/mTOR pathway. These findings provide a novel therapeutic approach for treating BRCA1-mutated ovarian cancer that overcomes PARP inhibitor resistance and enhances treatment results.