PAK4 kinase as a potential therapeutic target of the transcription factor p63-meditated squamous cell carcinomas of the pancreas.

Abstract

This study was undertaken to better understand the pathogenesis of squamous cell carcinoma (SCC) of the pancreas and to determine if inhibiting the p21-activated kinase 4 (PAK4) activity could be used for treating pancreatic SCCs. Here are the context of the research and preliminary results: Although significant research has been done on adenocarcinoma of the pancreas, the current understanding of pancreatic SCCs remains limited, and there is no known cure for it. We established a mouse model of pancreatic SCCs by over-expressing the transcription factor p63 in the pancreatic ductal epithelial-specific manner. Our working hypothesis was that dysregulation of p63-mediate transcriptional networks can lead to the development of pancreatic SCCs. As the stability of p63 is regulated at the protein level by phosphorylation, we searched for kinase that stabilizes p63 and identified PAK4 kinase. Although previous studies have shown that PAK4 is frequently overexpressed in ductal adenocarcinoma of the pancreas, the involvement of PAK4 in the pathogenesis of pancreatic SCCs remained unclear. We have demonstrated that suppression of the PAK4 kinase activity by a small molecule inhibitor reduced p63 levels in cellular models of pancreatic SCCs, leading to the complete suppression of their proliferation in vitro. These results indicate that PAK4 kinase can serve as a novel therapeutic target for some pancreatic SCCs and that PAK4-mediated stabilization/upregulation of the transcription factor p63 can be the key molecular event underlying the pathogenesis of pancreatic SCCs. We will use our mouse models in future studies to determine if administration of the PAK4 inhibitor in vivo can be used as an effective therapy for the treatment and prevention of the development of this most dangerous cancer subtype in human cancers.