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Updated: Jul 15, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
RAD50 deficiency is a predictor of platinum sensitivity in sporadic epithelial ovarian cancers
Adel Alblihy1, Muslim L Alabdullah1,2, Michael S Toss2
1Translational Oncology, Division of Cancer & Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, NG51PB, UK.
Abstract:
Intrinsic or acquired resistance seriously limits the use of platinating agents in advanced epithelial ovarian cancers. Increased DNA repair capacity is a key route to platinum resistance. RAD50 is a critical component of the MRN complex, a 'first responder' to DNA damage and essential for the repair of DSBs and stalled replication forks. We hypothesised a role for RAD50 in ovarian cancer pathogenesis and therapeutics. Clinicopathological significance of RAD50 expression was evaluated in clinical cohorts of ovarian cancer at the protein level (n = 331) and at the transcriptomic level (n = 1259). Sub-cellular localization of RAD50 at baseline and following cisplatin therapy was tested in platinum resistant (A2780cis, PEO4) and sensitive (A2780, PEO1) ovarian cancer cells. RAD50 was depleted and cisplatin sensitivity was investigated in A2780cis and PEO4 cells. RAD50 deficiency was associated with better progression free survival (PFS) at the protein (p = 0.006) and transcriptomic level (p < 0.001). Basal level of RAD50 was higher in platinum resistant cells. Following cisplatin treatment, increased nuclear localization of RAD50 was evident in A2780cis and PEO4 compared to A2780 and PEO1 cells. RAD50 depletion using siRNAs in A2780cis and PEO4 cells increased cisplatin cytotoxicity, which was associated with accumulation of DSBs, S-phase cell cycle arrest and increased apoptosis. We provide evidence that RAD50 deficiency is a predictor of platinum sensitivity. RAD50 expression-based stratification and personalization could be viable clinical strategy in ovarian cancers.
Insights
RAD50 deficiency predicts platinum sensitivity in ovarian cancer, improving progression-free survival. Lower RAD50 levels enhance cisplatin effectiveness by increasing DNA damage and apoptosis, suggesting its use in personalized treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Platinum-based chemotherapy resistance is a major challenge in advanced epithelial ovarian cancer.
- Increased DNA repair capacity, particularly double-strand break (DSB) repair, is a key mechanism driving platinum resistance.
- RAD50, a component of the MRN complex, plays a crucial role in DNA damage response and repair.
Purpose of the Study:
- To investigate the role of RAD50 in ovarian cancer pathogenesis and its potential as a therapeutic target.
- To evaluate the clinicopathological significance of RAD50 expression in ovarian cancer patients.
- To determine if RAD50 expression levels correlate with platinum sensitivity and treatment outcomes.
Main Methods:
- RAD50 protein and transcript levels were analyzed in clinical ovarian cancer cohorts (n=331 and n=1259, respectively).
- Sub-cellular RAD50 localization was assessed in platinum-sensitive and resistant ovarian cancer cell lines before and after cisplatin treatment.
- RAD50 was depleted using siRNA in resistant cells to evaluate its impact on cisplatin sensitivity, DNA damage, cell cycle, and apoptosis.
Main Results:
- RAD50 deficiency correlated with improved progression-free survival (PFS) at both protein and transcriptomic levels.
- Platinum-resistant cells exhibited higher basal RAD50 levels and increased nuclear localization upon cisplatin exposure compared to sensitive cells.
- RAD50 depletion in resistant cells enhanced cisplatin-induced cytotoxicity, DSB accumulation, S-phase arrest, and apoptosis.
Conclusions:
- RAD50 deficiency is a significant predictor of platinum sensitivity in epithelial ovarian cancer.
- RAD50 expression levels can potentially stratify patients for platinum-based therapies.
- Targeting RAD50 or utilizing its expression for patient stratification may represent a viable clinical strategy for personalized ovarian cancer treatment.
