Epigenetic adaptations and vulnerabilities in ovarian cancer drug-tolerant persister cells

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Abstract
High-grade serous ovarian carcinoma (HGSOC) recurs in most patients despite initial responses to chemotherapy and poly(ADP-ribose) polymerase inhibition. A leading explanation for the high rates of recurrence is the presence of minimal residual disease (MRD) comprised of drug-tolerant persister (DTP) cells that survive therapy through reversible epigenetic reprogramming. DTPs have various adaptations that enable them to tolerate therapy and eventually develop into resistant clones, including quiescence, metabolic and hypoxic stress responses, epithelial-mesenchymal plasticity, and immune evasion. Here, we discuss evidence from ovarian cancer of epigenetic mechanisms that coordinate DTP phenotypes, including DNA methylation, histone post-translational modifications, enhancer rewiring, and transcription factor gene-regulatory networks. Based on therapeutic vulnerabilities identified from increased resolution of DTPs, we highlight epigenetic therapies that are currently in clinical trials aimed at depleting MRD to delay or prevent relapse in HGSOC. Finally, we outline emerging technologies that have the potential to detect and monitor persister states in patients, including single-cell transcriptomic and epigenomic profiling, long-read sequencing, and spatial mapping of tumor biopsies.
Funding Information
  • Mayo Clinic (P50 CA136393)
  • Department of Defense Ovarian Cancer
  • Ovarian Cancer Academy (W81XWH2110475)
  • Department of Defense Ovarian Cancer Research Program (HT94252510458)
  • Canadian Institutes of Health Research (236-2024-2025-Q2-00473)
  • Foundation for Women Wellness
  • AACR Scholar-in-Training award
  • Mayo Medical Scientist Training Program (T32 GM145408)
  • Paul Calabresi Program in Clinical/Translational Research
  • Mayo Clinic Comprehensive Cancer Center (K12CA090628)
  • V Foundation for Cancer Research (V2026-006)

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