Targeting STAT3 signaling overcomes gefitinib resistance in non-small cell lung cancer.

Lung cancer is one of the most aggressive cancers with poor prognosis and high resistance rate. The family of signal transducer and activator of transcriptions (STATs) appears to modulate resistance in non-small cell lung cancer (NSCLC). In this work, we demonstrated that STAT3/ZEB1 is a critical axis in gefitinib resistance. STAT3-targeted inhibition therefore is a new potential therapeutic strategy for gefitinib resistance in lung cancer. Our small molecule screening identified a relatively specific STAT3-targeted inhibitor, LL1. Pharmacological and biochemical studies indicated that LL1 block the activation of STAT3 via inhibiting its phosphorylation. Further in vitro and in vivo studies elucidated that LL1 sensitizes the resistance cells to gefitinib through depleting STAT3 activity and blocking STAT3/ZEB1 signaling pathways. Little toxicity of LL1 was observed in animal models. All these favorable results indicated that LL1 is a chemotherapeutic adjuvant for gefitinib resistance in NSCLC.