Abstract 380: Chromatin rewiring and transcriptional plasticity drive a distinct dual-resistant state in ovarian cancer.

Abstract Background: Resistance to platinum-taxane combination therapy is a major clinical barrier in ovarian cancer (OC), yet the molecular determinants of dual resistance remain poorly defined. Single-agent cisplatin- or paclitaxel-resistant models are well characterized, but whether dual resistance represents an additive or fundamentally distinct state is unknown. Methods: We performed paired RNA-seq and ATAC-seq on A2780 parental cells and isogenic cisplatin-resistant (CpR), paclitaxel-resistant (TxR), and dual-resistant (TxCpR) derivatives. Differential expression, chromatin accessibility, motif enrichment, and enhancer-promoter integration analyses were used to identify transcriptional and epigenomic features unique to each resistance state. Results: CpR and TxR cells exhibited expected drug-specific adaptations, including upregulation of DNA repair genes (e.g., MLH1, LIG4) or cytoskeletal regulators and drug-efflux transporters (e.g., ABCB1, ALDH1A1). In contrast, TxCpR cells formed a distinct transcriptional and chromatin state, characterized by a hybrid epithelial-mesenchymal program, activation of developmental pathways, and selective retention of advantageous single-agent resistance traits. ATAC-seq revealed extensive remodeling of distal regulatory elements in TxCpR cells, with enrichment of MAFF, NFATC4, YY1, and ZNF549 motifs, implicating stress-response and chromatin-architectural regulators. Integrative analysis identified TxCpR-specific enhancers, including a CTCF-associated regulatory element near AIM2, suggesting emergent 3D chromatin restructuring that stabilizes dual-resistance transcriptional programs. Conclusions: Dual resistance to cisplatin and paclitaxel is not a composite of single-agent responses but a reprogrammed regulatory state driven by enhancer remodeling and coordinated transcription factor networks. This dataset provides a unique paired RNA-seq/ATAC-seq resource and identifies candidate enhancer and architectural dependencies that may be therapeutically targetable in multidrug-resistant OC. Citation Format: Won-Young Choi, Rachel Perkins, Jisun Kang, Haoxiang Lyu, Matthew S. Jung, Xiaoya Hou, Wei Li, Junming Yue, Wenjing Zhang. Chromatin rewiring and transcriptional plasticity drive a distinct dual-resistant state in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 380.