# Epigenetic Regulators as Therapeutic Targets in Pancreatic Ductal Adenocarcinoma

## TL;DR

This review explores how epigenetic changes contribute to pancreatic cancer and how targeting these changes could lead to better treatments.

## Contribution

The paper provides a comprehensive overview of epigenetic regulators in pancreatic cancer and their potential as therapeutic targets.

## Key findings

- Epigenetic alterations drive tumor progression and resistance in pancreatic cancer.
- Combining epigenetic therapies with existing treatments may improve outcomes.
- Pharmacological targeting of epigenetic regulators is an emerging strategy.

## Abstract

Pancreatic ductal adenocarcinoma is one of the deadliest cancers, largely due to late diagnosis and resistance to available treatments. Beyond genetic mutations, cancer cells are strongly influenced by epigenetic mechanisms—reversible chemical modifications that control gene activity without changing the DNA sequence. In pancreatic cancer, these epigenetic alterations reshape tumor behavior, promote spread, and enable resistance to therapy. This review summarizes current knowledge on key epigenetic proteins that regulate chromatin structure and gene expression in pancreatic cancer, including enzymes that write, read, or erase epigenetic marks. We also discuss emerging drugs targeting these regulators and highlight how combining epigenetic therapies with existing treatments may improve therapeutic outcomes. By integrating molecular biology, computational approaches, and preclinical models, this work aims to provide a framework for translating epigenetic discoveries into more effective diagnostic and therapeutic strategies for pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, driven by aggressive tumor biology, extensive intratumoral heterogeneity, and profound resistance to standard therapies. While recurrent genetic alterations such as KRAS mutations are central to PDAC initiation, growing evidence demonstrates that epigenetic dysregulation is a critical determinant of disease progression, cellular plasticity, immune evasion, and therapeutic failure. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA regulation, shape transcriptional programs without altering the underlying DNA sequence, rendering them dynamic and potentially reversible therapeutic targets. This review provides a comprehensive overview of key epigenetic proteins implicated in PDAC, encompassing writers, readers, and erasers of chromatin marks. Aberrant activity of histone methyltransferases and acetyltransferases, bromodomain-containing proteins, histone deacetylases, and demethylases orchestrates transcriptional reprogramming that promotes epithelial–mesenchymal transition, stem-like phenotypes, metabolic adaptation, and resistance to chemotherapy and radiotherapy. In parallel, epigenetic alterations within the tumor microenvironment contribute to stromal activation and immune suppression, further limiting therapeutic efficacy. We summarize recent advances in pharmacological targeting of epigenetic regulators and discuss the rationale for combination strategies integrating epigenetic inhibitors with cytotoxic agents, targeted therapies, and immunotherapies. Emphasis is placed on emerging experimental platforms—including patient-derived organoids, co-culture systems, and in vivo models—combined with multi-omic profiling and computational approaches to identify biomarkers of response and optimize therapeutic design. Collectively, this review highlights epigenetic regulation as a central and actionable vulnerability in PDAC and outlines future directions toward biomarker-guided, personalized epigenetic therapies aimed at overcoming resistance and improving clinical outcomes.