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Updated: Aug 13, 2025
Visualizing DNA Damage Repair Proteins in Patient-Derived Ovarian Cancer Organoids via Immunofluorescence Assays
Published on: February 24, 2023
DNA Damage Response Alterations in Ovarian Cancer: From Molecular Mechanisms to Therapeutic Opportunities
María Ovejero-Sánchez1,2,3, Rogelio González-Sarmiento1,2,3, Ana Belén Herrero1,2,3
1Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain.
Abstract:
The DNA damage response (DDR), a set of signaling pathways for DNA damage detection and repair, maintains genomic stability when cells are exposed to endogenous or exogenous DNA-damaging agents. Alterations in these pathways are strongly associated with cancer development, including ovarian cancer (OC), the most lethal gynecologic malignancy. In OC, failures in the DDR have been related not only to the onset but also to progression and chemoresistance. It is known that approximately half of the most frequent subtype, high-grade serous carcinoma (HGSC), exhibit defects in DNA double-strand break (DSB) repair by homologous recombination (HR), and current evidence indicates that probably all HGSCs harbor a defect in at least one DDR pathway. These defects are not restricted to HGSCs; mutations in ARID1A, which are present in 30% of endometrioid OCs and 50% of clear cell (CC) carcinomas, have also been found to confer deficiencies in DNA repair. Moreover, DDR alterations have been described in a variable percentage of the different OC subtypes. Here, we overview the main DNA repair pathways involved in the maintenance of genome stability and their deregulation in OC. We also recapitulate the preclinical and clinical data supporting the potential of targeting the DDR to fight the disease.
Insights
The DNA damage response (DDR) is crucial for genomic stability. Failures in DDR pathways are linked to ovarian cancer development, progression, and chemoresistance, suggesting DDR as a therapeutic target.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- The DNA damage response (DDR) maintains genomic stability against DNA-damaging agents.
- Alterations in DDR pathways are implicated in cancer, particularly ovarian cancer (OC).
- DDR defects contribute to OC onset, progression, and chemoresistance.
Purpose of the Study:
- To review DNA repair pathways and their deregulation in ovarian cancer.
- To summarize evidence for targeting DDR in OC treatment.
Main Methods:
- Literature review of DNA repair mechanisms.
- Analysis of DDR pathway alterations in various OC subtypes.
- Summary of preclinical and clinical data on DDR-targeting therapies.
Main Results:
- Approximately 50% of high-grade serous carcinomas (HGSCs) have homologous recombination (HR) repair defects.
- All HGSCs likely possess at least one DDR pathway defect.
- Mutations in ARID1A confer DNA repair deficiencies in endometrioid and clear cell OC subtypes.
Conclusions:
- DDR pathway deregulation is a common feature across OC subtypes.
- Targeting DDR presents a promising therapeutic strategy for ovarian cancer.
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