Targeting Epigenetic Regulators in Cancer Therapy: From Drug Resistance Mechanisms to Precision Interventions

Epigenetic regulators, including writers, readers, erasers, and remodelers, have emerged as pivotal targets in oncology drug development. Drugs targeting DNA methyltransferases (DNMTs), histone deacetylases (HDACs), and Bromodomain and Extra-Terminal (BET) proteins have achieved clinical success. However, the efficacy of these agents is often limited by intrinsic or acquired drug resistance. The mechanisms underlying this resistance are multifaceted and poorly understood, involving dynamic alterations in the epigenome and transcriptome. Recent advances highlight the role of non-canonical structures like R-loops and extrachromosomal DNA (ecDNA) in fostering epigenetic plasticity and therapeutic evasion. For instance, ecDNA hubs can amplify oncogenes and their associated enhancers, leading to hyper-aggressive transcription and resistance to BET inhibitors. Similarly, R-loop accumulation modulates DNA damage response and immune signaling, creating vulnerabilities for combination strategies. This Research Topic aims to dissect these complex mechanisms and explore novel pharmacological interventions to overcome them. We encourage submissions that employ cutting-edge techniques to elucidate these connections and translate findings into actionable biomarkers and precision therapeutic strategies.

The goal of this Research Topic is to create a comprehensive forum that bridges basic molecular mechanisms and clinical translation in epigenetic cancer therapy. We aim to collate original research and reviews that address the critical challenge of drug resistance. We seek to foster a deeper understanding of how tumor cells evade epigenetic drugs through mechanisms involving genome instability (e.g., R-loops, ecDNA), metabolic adaptation, and immune microenvironment remodeling. Ultimately, this collection will highlight innovative strategies—such as synthetic lethal interactions, biomarker-guided patient selection, and rational drug combinations—to preempt or overcome resistance and pave the way for more durable and personalized cancer treatments.

This Research Topic welcomes contributions on, but is not limited to, the following areas:

● Translational studies linking epigenetic mechanisms to clinical outcomes, biomarkers, and therapeutic resistance.

● Integration of multi-omics approaches and computational models to guide precision interventions.

● Innovative therapeutic strategies combining epigenetic drugs with other modalities, such as immunotherapy, chemotherapy, or targeted agents, to overcome resistance.

● Emerging therapeutic strategies targeting epigenetic vulnerabilities, including small molecules, RNA-based interventions, and CRISPR technologies.

● Synthetic lethal partnerships with mutations in epigenetic regulators or associated DNA repair pathways.

● Novel mechanisms of resistance to epigenetic drugs (e.g., BET, HDAC, EZH2 inhibitors)

● Discovery and validation of predictive biomarkers (e.g., genomic, epigenomic, or transcriptomic signatures) for patient stratification and monitoring response to epigenetic therapies.

Please note: Manuscripts consisting solely of bioinformatics, computational analysis, or predictions of public databases which are not accompanied by validation (independent clinical or patient cohort, or biological validation in vitro or in vivo, which are not based on public databases) are not suitable for publication in this journal.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Systematic Review
• Technology and Code

Keywords: Epigenetic therapy, Drug resistance, Epigenetic regulation, Precision oncology

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.