show Abstracthide AbstractTumor heterogeneity and therapy resistance are hallmarks of pancreatic ductal adenocarcinoma (PDAC). Emerging evidence supports treatment-induced resistance to be a multifactorial process mediated by cellular plasticity involving epigenetic regulation. Here, we used a multi-omics approach to analyze in detail molecular mechanisms underlying MEK inhibitor (MEKi) resistance. Therefore, we characterized different cell stages (parental, MEKi resistant, reverted after different passages of drug withdrawal) in primary cell lines derived from a genetic PDAC mouse model, thereby minimizing inter-individual heterogeneity that could distort genome-wide analyses. Overall design: RNA-sequencing of six primary murine pancreatic ductal adenocarcinoma cell lines. Three to four differrent cell stages (MEKi treatment naive, MEKi resistant, MEKi resistant and drug withdrawal for 5 or 12 passages) were analyzed