GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE300nnn/GSE300008/suppl/filelist.txtftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE300nnn/GSE300008/suppl/GSE300008_RAW.tarftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE300nnn/GSE300008/primaryOK200GenomicsMus musculusGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE300008GEOGSEfalseDecoding the response to a PP2A inhibitor in pancreatic cancerThe high failure rate of a cancer drug from target definition to clinical implementation highlights the need to prioritize context-specific targets. 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. We provide evidence for a PP2A inhibitor-sensitive subtype of PDAC and offer detailed insights into the cellular response induced by PP2A inhibitors.2026/06/18GSE300008GSM9052329GSM9052338GSM9052337GSM9052324GSM9052323GSM9052332GSM9052331GSM905233024247300008Mus musculus[42266180]