Abstract 5718: Molecular determinants of platinum resistance in ovarian cancer: Linking PARP1, DNMT1, γ-GCS expression, and LINE1 hypermethylation

Abstract Background: Ovarian cancer is a leading cause of gynecological cancer-related mortality worldwide. Alarmingly, 80% of patients are diagnosed at an advanced stage (FIGO stage III-IV), where the prognosis is poor. The current standard of care for advanced epithelial ovarian cancer (EOC) includes cytoreductive surgery followed by taxane and platinum-based chemotherapy. Despite initial responses, resistance to platinum remains a significant cause of treatment failure and relapse in EOC. This study aims to investigate the molecular underpinnings of platinum resistance by examining the expression and enzymatic activity of PARP1 and γ-GCS and their correlation with DNA methylation patterns in ovarian cancer. Based on existing evidence, we hypothesize that inhibition of PARP1 or γ-GCS may enhance cisplatin (CDDP) sensitivity, offering new therapeutic opportunities. Understanding these mechanisms could pave the way for innovative strategies to overcome chemotherapy resistance in ovarian cancer. Material and Methods: Peripheral Blood (PB) and Ascitic Fluid (AS) samples were collected from 20 EOC patients. The cohort was divided into two groups: Group A (n=10) included treatment-naive baseline patients, and Group B (n=10) comprised relapsed patients. Additionally, healthy control samples (n=10) were collected for comparison. The study involved: 1 Gene Expression Analysis: Differential expression levels of PARP1, DNMT1, and γ-GCS were evaluated using qPCR. 2 Enzymatic Activity Measurement: Glutathione (GSH) activity was quantified using ELISA. 3 Global DNA Methylation Assessment: LINE1 methylation levels were measured via pyrosequencing to examine epigenetic changes. The resulting data were correlated with clinico-pathological parameters, including age, stage, CA markers, and hematological indices. Statistical analysis was conducted using GraphPad Prism 6, and a p-value < 0.05 was considered statistically significant. Results: High γ-GCS expression increases glutathione levels in newly diagnosed ovarian cancer patients, potentially driving platinum resistance. Consistent LINE1 hypermethylation across patients, influenced by various factors, highlights its potential as both a biomarker and a therapeutic target, paving the way for strategies to overcome chemotherapy resistance. Abbreviations: Epithelial Ovarian Cancer (EOC), cisplatin (CDDP), Glutathione (GSH), Gamma Glutamyl Cysteine Synthetase (γ-GCS), Poly (ADP ribosyl) polymerase-1 (PARP1), Enzyme-linked immunosorbent assay (ELISA), Quantitative Polymerase Chain Reaction (qPCR), DNA methylation LINE1, Peripheral Blood (PB), Ascitic Fluid (AS). Citation Format: Luxmi Devi, Ashok Kumar, Lalit Kumar. Molecular determinants of platinum resistance in ovarian cancer: Linking PARP1, DNMT1, γ-GCS expression, and LINE1 hypermethylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5718.