Chromatin rewiring and transcriptional plasticity define a distinct platinum-taxane dual-resistant state in ovarian cancer

Ovarian cancer (OC) remains the most lethal gynecologic malignancy, and platinum-taxane combination therapy is the global first-line standard of care for advanced disease. However, resistance to platinum-taxane combination therapy is a major clinical barrier in ovarian cancer (OC), yet the molecular basis of dual resistance remains unresolved. Therefore, defining the molecular mechanisms that drive resistance to combined platinum-taxane therapy is essential for identifying new therapeutic targets and improving patient outcomes. We generated matched RNA-seq and ATAC-seq profiles from parental A2780 cells and derivatives exhibiting functional resistance to platinum (CpR), taxane (TxR), or both agents (TxCpR). We integrated differential gene expression with chromatin accessibility, annotated regulatory elements using ENCODE cCREs, and performed motif enrichment to infer candidate transcription factor programs. We found that CpR and TxR cells displayed the expected drug-specific transcriptional profiles. CpR cells upregulated DNA repair genes, whereas TxR cells showed activation of pathways associated with paclitaxel adaptation, including cytoskeletal regulation and ABCB1-mediated efflux. In contrast, TxCpR cells adopted a distinct regulatory state, separate from CpR and TxR. They exhibited broad enhancer remodeling and enriched accessibility at developmental and morphogenesis-associated loci. Motif analysis identified stress-responsive (MAFF (MAF bzip transcription factor F), NFATC4 (Nuclear factor of activated T-cells 4)) and architectural (YY1 (Yin-Yang 1), ZNF549 (Zinc finger protein 549), CTCF (CCCTC-binding Factor)) transcription factors as candidate regulators of this state. Integrated analysis of RNA-seq and ATAC-seq identified TxCpR-associated candidate distal regulatory elements, including an accessible CTCF motif-containing region near AIM2 (Absent in Melanoma 2) gene, highlighting AIM2 -proximal regions as candidates for further functional investigation. Dual platinum-taxane resistance is accompanied by integrated transcriptional plasticity and chromatin rewiring, consistent with a regulatory state that is distinct from single-agent resistance. To our knowledge, this dataset represents the first paired transcriptomic–epigenomic map of all four A2780 states, and identifies candidate transcriptional and distal regulatory elements that may be exploited to target multidrug resistance in OC.