Wippel, Catherine Wegner

Objective Pancreatic ductal adenocarcinoma (PDAC) displays a remarkable propensity towards therapy resistance. However, molecular epigenetic and transcriptional mechanisms enabling this are poorly understood. In this study, we aimed to identify novel mechanistic approaches to overcome or prevent resistance in PDAC. Design We used in vitro and in vivo models of resistant PDAC and integrated epigenomic, transcriptomic, nascent RNA and chromatin topology data. We identified a JunD-driven subgroup of enhancers, called interactive hubs (iHUBs), which mediate transcriptional reprogramming and chemoresistance in PDAC. Results iHUBs display characteristics typical for active enhancers (H3K27ac enrichment) in both therapy sensitive and resistant states but exhibit increased interactions and production of enhancer RNA (eRNA) in the resistant state. Notably, deletion of individual iHUBs was sufficient to decrease transcription of target genes and sensitise resistant cells to chemotherapy. Overlapping motif analysis and transcriptional profiling identified the activator protein 1 (AP1) transcription factor JunD as a master transcription factor of these enhancers. JunD depletion decreased iHUB interaction frequency and transcription of target genes. Moreover, targeting either eRNA production or signaling pathways upstream of iHUB activation using clinically tested small molecule inhibitors decreased eRNA production and interaction frequency, and restored chemotherapy responsiveness in vitro and in vivo. Representative iHUB target genes were found to be more expressed in patients with poor response to chemotherapy compared with responsive patients. Conclusion Our findings identify an important role for a subgroup of highly connected enhancers (iHUBs) in regulating chemotherapy response and demonstrate targetability in sensitisation to chemotherapy.

A man in his 70s with a history of fatigue, abdominal pain, and a palpable abdominal mass was found to have a peritoneal desmoid tumour. One year after diagnosis, he was prescribed sorafenib to limit tumour growth. Two months later, he developed dyspnoea on exertion and lower extremity weakness and was reported to have supine hypertension and orthostatic hypotension. On formal autonomic testing, he was noted to have severely impaired sympathetic responses and marked orthostatic hypotension without appropriate chronotropic response. A decision to hold sorafenib was made, and treatment was started with graduated compression stockings, liberal fluid and sodium intake, and midodrine. The patient had a modest and gradual improvement in his symptoms. To our knowledge, this is the first reported case of orthostatic hypotension related to sorafenib or any vascular endothelial growth factor inhibitors.