CPAMD8 and EGR1 are Potential Prognostic Signature Genes Associated With Olaparib and Niraparib Resistance in Ovarian Cancer

Background: Poly (ADP-ribose) polymerase inhibitors (PARPis) are effective adjunctive therapies for ovarian cancer (OC). However, drug resistance remains a significant clinical challenge. Current research focuses on target expression and functional changes in established resistant cell lines. Yet, a comprehensive analysis of transcriptomic alterations over time after PARPis exposure is lacking. This study aims to investigate the transcriptomic changes in OC cell lines following prolonged PARPis treatment and to identify potential resistance biomarkers. Methods: SKOV3 and OVCAR8 cell lines were treated with Olaparib and Niraparib for 2, 3 and 6 months, and then RNA sequencing (RNA-seq) was performed. Differentially expressed genes (DEGs) were identified through “limma” analysis, following the conduction of function enrichment analysis. Survival analysis was performed using The Cancer Genome Atlas (TCGA) data to correlate DEG expression with clinical outcomes. To validate the identified key resistance genes, we modulated their expression using specific siRNAs for knockdown and overexpression vectors. We performed these experiments in ovarian cancer cells following long-term culture with PARPis. Models included SKOV3 and OVCAR8 cells, which were maintained for 6 months with either Niraparib (SKOV3Nira₆M, OVCAR8Nira₆M) or Olaparib (SKOV3Ola₆M, OVCAR8Ola₆M). We then assessed proliferation and viability to confirm the functional relevance of these genes to PARPis sensitivity in ovarian cancer. Results: The transcriptional profiles of the same type of OC cells stimulated by Niraparib and Olaparib for 6 months were highly similar. After SKOV3 cells were treated with PARPis for 6 months, 59 DEGs showed consistent changes, while 103 DEGs were identified in OVCAR8 cells (adjusted p 2 fold change| >1). These DEGs were enriched in biological processes such as epithelial cell differentiation (p p p CPAMD8 (p EGR1 were specifically upregulated in SKOV3 (adjusted p p CPAMD8 and EGR1 were significantly elevated in SKOV3 and OVCAR8 cells following 6 months of maintenance culture with PARPis. Building on these findings, functional studies demonstrated that enforced overexpression of CPAMD8 or EGR1 in these PARPis-persistent cells markedly enhanced cell viability. In contrast, knockdown of CPAMD8 or EGR1 expression effectively suppressed cell viability. Conclusion: CPAMD8 and EGR1 were identified as potential biomarkers of mild drug resistance and were associated with poorer survival.