Regulation of Pancreatic Ductal Adenocarcinoma Subtypes by Chromatin Proteins Determines Sensitivity to Inhibitors of Transcriptional Cyclin-dependent Kinases.

Abstract

Pancreatic ductal adenocarcinoma (PDA) subtype classifications were originally defined by transcriptional differences between two groups, known as the basal and classical PDA subtypes. The biological differences between these two subtypes goes beyond just transcriptional differences as the transcriptome is defined by the epigenome, therefore epigenetic changes including chromatin regulation, control transcriptional expression of the gene groups used to define the basal and classical subtypes. In this dissertation, I discuss how different epigenetic regulators contribute to the basal and classical PDA cell states and that disruptions to these cell states can alter cellular plasticity. I then show that regulation of these subtype-specific cell states defines the cells’ ability to respond to stressors such as transcriptional inhibitors. Further investigation of transcriptional inhibitors as a therapeutic option for PDA, led us to uncover that PDA presents with a subtype-specific sensitivity to inhibitors of transcriptional cyclin-dependent kinases (CDKs). Moreover, we define that altering chromatin regulation and disrupting PDA cell state can modify PDA sensitivity to transcriptional CDK inhibitors. This work presents novel insights into the therapeutic potential of transcriptional CDK inhibitors in the treatment of PDA patients and how regulation of chromatin states can be used to adjust sensitivity of PDA tumors to the inhibitors.