The "hallmarks" of pancreatic ductal adenocarcinoma (PDAC) include 
proliferative, invasive, and metastatic tumor cells and an associated dense 
desmoplasia comprised of fibroblasts, pancreatic stellate cells, extracellular 
matrix, and immune cells. The oncogenically activated pancreatic epithelium and 
its associated stroma are obligatorily interdependent, with the resulting 
inflammatory and immunosuppressive microenvironment contributing greatly to the 
evolution and maintenance of PDAC. The peculiar pancreas-specific tumor 
phenotype is a consequence of oncogenes hacking the resident pancreas 
regenerative program, a tissue-specific repair mechanism regulated by discrete 
super enhancer networks. Defined as genomic regions containing clusters of 
multiple enhancers, super enhancers play pivotal roles in cell/tissue 
specification, identity, and maintenance. Hence, interfering with such super 
enhancer-driven repair networks should exert a disproportionately disruptive 
effect on tumor versus normal pancreatic tissue. Novel drugs that directly or 
indirectly inhibit processes regulating epigenetic status and integrity, 
including those driven by histone deacetylases, histone methyltransferase and 
hydroxylases, DNA methyltransferases, various metabolic enzymes, and bromodomain 
and extraterminal motif proteins, have shown the feasibility of disrupting super 
enhancer-dependent transcription in treating multiple tumor types, including 
PDAC. The idea that pancreatic adenocarcinomas rely on embedded super enhancer 
transcriptional mechanisms suggests a vulnerability that can be potentially 
targeted as novel therapies for this intractable disease. Clin Cancer Res; 
23(7); 1647-55. ©2017 AACRSee all articles in this CCR Focus section, 
"Pancreatic Cancer: Challenge and Inspiration."