Use of histone deacetylase inhibitors (HDACis) in pancreatic ductal adenocarcinoma (PDAC): A narrative review

This narrative review paper examines the use and potential benefits of histone deacetylase inhibitors (HDACis) in pancreatic ductal adenocarcinoma (PDAC) as a combinational therapy. The paper provides a concise overview of the epigenetic events and their effects on gene expression in PDAC, followed by a summary of selected preclinical and clinical studies, demonstrating the efficacy of HDACis as combinatorial treatments. The current therapeutic approach in PDAC includes low-efficacy combination therapies, mainly as a palliative treatment, due to delayed diagnosis, rapid disease progression, and development of metastases. The tumor mutational burden and several epigenetic modifications shape tumor characteristics, regulate the gene expression, and alter the cell cycle. Epigenetic modifications at lysine residues of histones, including acetylation, are mediated by histone acetyltransferases and counteracted by HDACs. HDACis are approved as monotherapy in cutaneous T-cell lymphoma and are potentially effective when administered in combination with other therapies in solid tumors. In particular, combinations of HDACis with tyrosine kinases inhibitors, MEK inhibitors, PI3K inhibitors, 13-cis-retinoic acid, EZH2 inhibitors, and BET inhibitors appear to suppress epithelial–mesenchymal transition, promote apoptosis, and increase overall survival in patients with PDAC.