Feedback activation of EGFR is the main cause for STAT3 inhibition-irresponsiveness in pancreatic cancer cells.

Pancreatic cancer is one of the world's leading causes of cancer-related death. Activation of STAT3 has been reported as a major contributor in pancreatic cancer tumorigenesis and chemoresistance. However, treatment of advanced pancreatic cancer patients with STAT3 inhibitors often meets drug resistance and heterogeneous response. We found that EGFR activation is a main cause for resistance to STAT3 inhibitors in pancreatic cancer cells, regardless of KRAS mutation status. Mechanistically, inhibition of STAT3 promotes STAT1- and STAT4-mediated TGF-α expression, leading to activation of the EGFR pathway. Combined treatment of pancreatic cancer cells with EGFR and STAT3 inhibitors persistently blocks EGFR and STAT3 signaling, and exerts synergistic antitumor activity both in vitro and in vivo, with or without KRAS mutation. Our results indicate that reciprocal cross-talk between STAT3 and EGFR pathways is a key molecular mechanism leading to resistance in pancreatic cancer cells. Furthermore, the study shows that combined inhibition of both EGFR and STAT3 might overcome drug resistance encountered during treatment with single agent alone. This study suggests an improved therapeutic strategy, through combined treatment with STAT3 and EGFR inhibitors, for pancreatic cancer patients.