Activating transcriptional elongation as a strategy to treat aggressive mesenchymal pancreatic ductal adenocarcinoma

The high fail rate characterizing the path of a cancer drug from the target definition to the clinic implements the need to prioritize context-specific targets, work on biomarkers, and decipher a detailed cellular response induced by the drug. Context-specific target priority scores for pancreatic ductal adenocarcinoma (PDAC) showed a top rank for the catalytical active subunit of the protein phosphatase 2A (PP2A). Therefore, we characterized the PP2A inhibitor LB100-induced response in PDAC models cross-species and models. We observed that undifferentiated, mesenchymal PDAC cells are susceptible to LB100-mediated death. CRISPR/Cas9-based genetic screens revealed the contribution of various transcription cycle components to the LB100 response. We provide evidence that PP2A antagonizes CDK9 function, a major regulator of the RNA polymerase II pausing checkpoint and driver of transcriptional elongation, and limits the expression of a conserved gene expression program. The transcriptional output of this program upon LB100 treatment is distinctly higher in mesenchymal PDAC cells, leading to a breakdown of cellular homeostatic networks, an unfolded protein response, the formation of stress granules, autophagy, and cell death. Our study provides evidence for a PP2A inhibitor sensitivity subtype of PDAC and showed detailed insight into cellular response induced by PP2A inhibitors. Our findings are important for the further development of PP2A inhibitor-based therapies and the design and testing of rational combinations.