Targeting STAT3 Signaling Facilitates Responsiveness of Pancreatic Cancer Cells to Chemoradiotherapy

SIMPLE SUMMARY: Preoperative chemoradiotherapy (CRT) has emerged as a potential therapeutic strategy to increase the fraction of patients with pancreatic ductal adenocarcinoma (PDAC) who are candidates for surgical resection. However, treatment response is heterogeneous and ranges from complete response to progression. In this study, we uncovered that the transcription factor STAT3 mediates CRT resistance in PDAC cell lines with high IL-6/STAT3 signaling activity. If further validated, pharmacological inhibition of the IL-6/STAT3 pathway may represent a promising therapeutic strategy to increase responsiveness of PDAC to preoperative CRT. ABSTRACT: The debate is ongoing regarding the potential role of preoperative chemoradiotherapy (CRT) for patients with pancreatic ductal adenocarcinoma (PDAC), and whether it should be reserved for borderline resectable or unresectable tumors. However, treatment response is heterogeneous, implicating the need to unveil and overcome the underlying mechanisms of resistance. Activation of the transcription factor STAT3 was recently linked to CRT resistance in other gastrointestinal cancers such as rectal and esophageal cancers, but its role in PDAC needs to be clarified. Protein expression and phosphorylation of STAT3 was determined in PDAC cell lines and connected to transcriptional activity measured by dual-luciferase reporter gene assays. Inhibition of STAT3 signaling was achieved by RNAi or the small-molecule inhibitor napabucasin. We observed a positive correlation between STAT3 signaling activity and CRT resistance. Importantly, genetical and pharmacological perturbation of the IL-6/STAT3 pathway resulted in CRT sensitization specifically in those cell lines, in which STAT3 activity was augmented by IL-6. In conclusion, our data underscore the general importance of IL-6/STAT3 signaling for CRT resistance and suggest that pathway inhibition may represents a putative treatment strategy in order to increase the fraction of patients with PDAC who are candidates for surgical approaches.