Abstract A025: Molecular signature of cisplatin resistance in ovarian cancer identifies therapeutic opportunities for re-sensitization

Abstract Cisplatin remains a standard first-line therapy for epithelial ovarian cancer; however, the development of chemoresistance leads to poor prognosis and high recurrence rates. Kaplan–Meier analysis of patient data (TCGA) revealed that cisplatin-sensitive tumors are associated with significantly improved overall survival, underscoring the need for strategies to overcome resistance in clinical settings. To investigate the underlying mechanisms, we conducted a comprehensive bioinformatics analysis of publicly available GEO datasets from cisplatin-treated ovarian cancer patients (n = 255). This analysis identified six key molecular drivers of resistance: ZBTB33 (Kaiso), pregnane X receptor (PXR), NF-κB, HER2 (ERBB2), P-glycoprotein (P-gp/ABCB1), and HIF1A. These targets were validated in ovarian tumor specimens via immunohistochemistry, confirming elevated expression in chemo-resistant disease. Additionally, the quantitative real-time PCR analysis confirms the transcriptional upregulation of the six resistance-associated genes in cisplatin-resistant SKOV3 and OVCAR-5 ovarian cancer cells, consistent with the IHC findings. The average fold change in mRNA transcripts ranged from 2.4 for P-glycoprotein (P-gp) to 5 for both NF-kB and Kaiso (ZBTB33). Although less well studied in ovarian cancer, Kaiso (ZBTB33) is known to regulate EMT and tumor invasion in other solid tumors. Functional studies using SKOV3 and OVCAR-5 cell lines demonstrated that knockdown of Kaiso (ZBTB33) via RNA interference significantly increased cisplatin-induced cell death, indicating a direct role in therapeutic resistance. Furthermore, we investigated the synergistic effects of combining SDA, a plant-based omega-3 fatty acid known to inhibit NF-κB, and cisplatin on the cell death of SKOV3 and OVCAR-5 cell lines, comparing the results to those of each compound used individually. Interestingly, co-treatment with stearidonic acid (SDA) synergistically enhanced the cytotoxicity of cisplatin at a lower dose in both cell models. These findings reveal a clinically relevant resistance signature and highlight the therapeutic potential of combinatorial strategies that target both transcriptional regulators (e.g., Kaiso) and inflammatory signaling (e.g., NF-κB). Dual targeting of these pathways may resensitize tumors to cisplatin and improve outcomes for patients with advanced ovarian cancer. Citation Format: Mahmoud Mansour, Sabrina Van Ginkel, Maaz Kamal Alata, Ibrahim Bani, Isra Elhussin. Molecular signature of cisplatin resistance in ovarian cancer identifies therapeutic opportunities for re-sensitization [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A025.