Epigenetics in Pancreatic Ductal Adenocarcinoma: Impact on Biology and Utilization in Diagnostics and Treatment

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with high potential of metastases and therapeutic resistance. Although genetic mutations drive PDAC initiation, they alone do not explain its aggressive nature. Epigenetic mechanisms, including aberrant DNA methylation and histone modifications, significantly contribute to inter- and intratumoral heterogeneity, disease progression and metastasis. Thus, increased understanding of the epigenetic landscape in PDAC could offer new potential biomarkers and tailored therapeutic approaches. In this review, we shed light on the role of epigenetic modifications in PDAC biology and on the potential clinical applications of epigenetic biomarkers in liquid biopsy. In addition, we provide an overview of clinical trials assessing epigenetically targeted treatments alone or in combination with other anticancer therapies to improve outcomes of patients with PDAC.

Keywords: BET inhibitors; DNMT inhibitors; EZH2 inhibitors; HDAC inhibitors; cfDNA methylation; epigenetics; pancreatic ductal adenocarcinoma; retinoids.

Figure 1

Development of new biomarkers and therapeutic approaches for cancer treatment: A bi-directional process. Bench to bedside; Experimental models used in cancer research can vary from 2D-cell culture to murine in vivo models to more complex 3D patient-derived cancer organoids. These models can identify cancer-related genetic and epigenetic signatures using a plethora of sequencing and targeted qPCR techniques, which can then be utilized to predict novel cancer biomarkers and therapeutic targets to be eventually translated into clinical practice. Bedside to bench; the poor performance of some biomarkers or the emergence of drug resistance to anticancer agents may contribute to their failure to reach the clinic. This urges preclinical studies to test new biomarker panels or to find new strategies to overcome drug resistance with the aim to improve therapeutic outcomes of cancer patients.