Decoding the response to a PP2A inhibitor in pancreatic cancer

Here, we identify PP2A as an important target in pancreatic ductal adenocarcinoma (PDAC) by cancer-dependency scores. We characterized how inhibition of PP2A with the clinical grade inhibitor LB100 affects PDAC cells.

Mesenchymal PDAC cells are highly susceptible to LB100-induced death. CRISPR-Cas9 drop-out screens revealed the contribution of the transcription cycle, splicing, or translation to the LB100 response. Mechanistically, PP2A inhibition disables the RNA polymerase II pause checkpoint, leading to CDK9-mediated transcriptional elongation linked to a ER stress response correlated with the formation of stress granules, autophagy, and cell death.