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Updated: Nov 10, 2025
Visualizing DNA Damage Repair Proteins in Patient-Derived Ovarian Cancer Organoids via Immunofluorescence Assays
Published on: February 24, 2023
Genomic, Transcriptomic, and Functional Alterations in DNA Damage Response Pathways as Putative Biomarkers of
Sweta Sharma Saha1, Lucy Gentles1, Alice Bradbury1
1Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
Abstract:
Defective DNA damage response (DDR) pathways are enabling characteristics of cancers that not only can be exploited to specifically target cancer cells but also can predict chemotherapy response. Defective Homologous Recombination Repair (HRR) function, e.g., due to BRCA1/2 loss, is a determinant of response to platinum agents and PARP inhibitors in ovarian cancers. Most chemotherapies function by either inducing DNA damage or impacting on its repair but are generally used in the clinic unselectively. The significance of HRR and other DDR pathways in determining response to several other chemotherapy drugs is not well understood. In this study, the genomic, transcriptomic and functional analysis of DDR pathways in a panel of 14 ovarian cancer cell lines identified that defects in DDR pathways could determine response to several chemotherapy drugs. Carboplatin, rucaparib, and topotecan sensitivity were associated with functional loss of HRR (validated in 10 patient-derived primary cultures) and mismatch repair. Two DDR gene expression clusters correlating with treatment response were identified, with PARP10 identified as a novel marker of platinum response, which was confirmed in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. Reduced non-homologous end-joining function correlated with increased sensitivity to doxorubicin, while cells with high intrinsic oxidative stress showed sensitivity to gemcitabine. In this era of personalised medicine, molecular/functional characterisation of DDR pathways could guide chemotherapy choices in the clinic allowing specific targeting of ovarian cancers.
Insights
Defects in DNA damage response (DDR) pathways predict chemotherapy response in ovarian cancer. Molecular characterization of DDR can guide personalized treatment selection for better outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Defective DNA damage response (DDR) pathways are hallmarks of cancer, offering therapeutic targets and predictive biomarkers.
- Homologous Recombination Repair (HRR) defects, like BRCA1/2 loss, predict platinum and PARP inhibitor response in ovarian cancer.
- The role of HRR and other DDR pathways in predicting response to diverse chemotherapies remains largely unexplored.
Purpose of the Study:
- To investigate the association between DNA damage response (DDR) pathway status and sensitivity to various chemotherapy drugs in ovarian cancer.
- To identify novel biomarkers within DDR pathways that predict treatment response.
- To explore the potential of DDR pathway characterization for guiding personalized chemotherapy selection in ovarian cancer.
Main Methods:
- Genomic, transcriptomic, and functional analyses of DDR pathways in 14 ovarian cancer cell lines.
- Validation of HRR defect-associated drug sensitivity in 10 patient-derived primary cultures.
- Analysis of The Cancer Genome Atlas (TCGA) ovarian cancer cohort for biomarker validation.
Main Results:
- Defects in DDR pathways determined sensitivity to multiple chemotherapy drugs.
- Functional loss of HRR correlated with carboplatin, rucaparib, and topotecan sensitivity.
- PARP10 emerged as a novel platinum response marker, and reduced non-homologous end-joining predicted doxorubicin sensitivity.
Conclusions:
- Molecular and functional characterization of DDR pathways can predict ovarian cancer response to various chemotherapies.
- PARP10 is a potential predictive biomarker for platinum-based chemotherapy.
- DDR pathway profiling offers a promising strategy for personalized medicine in ovarian cancer treatment.
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