Alantolactone sensitizes human pancreatic cancer cells to EGFR inhibitors through the inhibition of STAT3 signaling.

Several studies have implicated the feedback activation of signal transducer and activator of transcription 3 (STAT3) as a new cancer drug-resistance mechanism and linked it to the failure of epidermal growth factor receptor (EGFR)-targeted therapies. In this study, we discovered that Alantolactone, a natural sesquiterpene lactone, potently inhibited human pancreatic cancer cells and suppressed constitutively activated STAT3. In contrast, Alantolactone had little effect on the EGFR pathway. Moreover, combination of Alantolactone and an EGFR inhibitor, Erlotinib or Afatinib, demonstrated a remarkable synergistic anti-cancer effect against pancreatic cancer cells both in vitro and in vivo. Our results suggested that Alantolactone could sensitize human pancreatic cancer cells to EGFR inhibitors possibly through down-regulating the STAT3 signaling. Alantolactone, when combined with other EGFR targeted agents, could be further developed as a potential therapy for pancreatic cancer.