Constitutive activation of
signal transducer and activator of transcription 3 (STAT3) is a common feature in human
non-small cell lung cancer (NSCLC). STAT3 plays an important role in
cancer progression as a driver oncogene and acquired resistance of targeted
therapies as an alternatively activated pathway. W2014-S with pharmacophore structure of
imidazopyridine, which was firstly reported to be utilized in STAT3 inhibitor discovery, was screened out as a potent STAT3 inhibitor from a library of small molecules. The aim of this study is to investigate the antitumor activities and mechanisms of W2014-S in NSCLC and effect on
epidermal growth factor receptor-
tyrosine kinase inhibitors (EGFR-TKIs) resistance in vitro and in vivo. Methods: SPR analysis, Co-immunoprecipitation, confocal microscope imaging, and
luciferase report gene assays were utilized to determine the mechanisms. Cell viability, colonial survival, wound healing, cell invasion assay, human
cancer cell xenografts and PDX
tumor xenografts were used to determine antitumor activities. Results: W2014-S disrupted STAT3 dimerization and selectively inhibited aberrant STAT3 signaling in NSCLC cell line. W2014-S strongly suppressed proliferation, survival, migration and invasion of
lung cancer cells with aberrant STAT3 activation and inhibited the growth of human NSCLC cell xenografts and PDX
tumor xenografts in mouse model. Furthermore, W2014-S significantly sensitized resistant NSCLC cell line to
gefitinib and
erlotinib in vitro and enhances the anti-
tumor effect of
gefitinib in TKI-resistant
lung cancer xenografts in vivo. Conclusions: Our study has provided a novel STAT3 inhibitor with significant anti-
tumor activities in NSCLC and suggests that combination of STAT3 inhibitor such as W2014-S with
gefitinib could serve as a promising strategy to overcome EGFR-TKIs acquired resistance in NSCLC patients.