Sunitinib Synergizes with Cisplatin by Suppressing DNA Repair Pathways in High-Grade Serous Ovarian Carcinoma Cells

Abstract Background: High-grade serous ovarian carcinoma (HGSOC) frequently develops resistance to platinum-based chemotherapy such as cisplatin, leading to high mortality. Sunitinib, a multi-target Receptor tyrosine kinase inhibitor, has shown potential in the treatment of ovarian carcinoma (OC). However, the synergistic effects between cisplatin and sunitinib, and the sensitization mechanism of sunitinib in HGSOC are not yet understood. Methods: The anti-tumor effects of sunitinib on HGSOC cells were assessed using CCK-8, EdU, colony formation, wound healing, Transwell, and flow cytometry assays. RNA sequencing was performed on sunitinib-treated cells, followed by differential expression, enrichment, and protein-protein interaction network (PPI) analyses. Genes on cisplatin sensitivity were predicted using the CellMiner and GEPIA3 databases. Synergy between sunitinib and cisplatin was evaluated using SynergyFinder 3.0, and DNA damage was assessed by γ-H2AX expression. Results: Sunitinib significantly inhibited proliferation, migration, and invasion in HGSOC cells, while further inducing cell cycle arrest, promoting necrosis. Besides, sunitinib downregulated critical DNA damage repair pathways, including homologous recombination, fanconi anemia, and base excision repair. Furthermore, sunitinib synergizes with cisplatin in HGSOC cells, enhancing DNA damage compared to monotherapy. Additionally, we screened out 25 sunitinib-downregulated core genes (SDCs). Drug-sensitivity analyses showed that higher SDCs expression was significantly associated with cisplatin resistance in OC. Notably, in cisplatin-resistant HEY-A8/DDP cells, sunitinib displayed stronger cytotoxicity than cisplatin. Conclusion: Sunitinib induces cell-cycle arrest and necrosis. In addition, sunitinib synergized with cisplatin and enhanced cisplatin sensitivity by impairing DNA repair pathways. Drug-sensitivity analyses showed that SDCs are associated with cisplatin resistance in OC, suggesting that sunitinib may help overcome cisplatin chemoresistance. Notably, sunitinib retains substantial cytotoxic activity in cisplatin-resistant cells. Together, these findings suggest that the sunitinib–cisplatin combination is a promising strategy to overcome cisplatin resistance in HGSOC.