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Background Insulin-like growth factor 1 (IGF-1) signaling pathway has been reported to be one of the molecular mechanisms by which acquired resistance to the first generation of epidermal growth factor receptor (EGFR)-Tyrosine kinase inhibitors (TKIs) in patients with EGFR mutations.This study aims to investigate the molecular mechanism in acquired resistance to gefitinib in non-small cell lung cancer cells with wild-type EGFR.Methods Human lung adenocarcinoma cell line A549 was used to establish gefitinib-resistant subline (A549/GR) by chronic exposure to a series of increased concentrations of gefitinib.Cell proliferation was measured with a Cell Counting Kit-8.Mutation analysis of EGFR and IGF-1R was performed via direct sequencing.Gene expression of IGF-1R and its downstream signaling molecules (including ERK1 and AKT1) were analyzed by quantitative real-time PCR (qRT-PCR).Results Gefitinib-resistant cell line A549/GR was six fold more resistant to gefitinib than parental ceils, and showed a markedly increased in proliferation rote.In addition, neither acquired mutations in exons 18-21 of the EGFR nor mutations in the tyrosine ldnase of IGF-1R were detected in A549/GR cells.Subsequently, compared with parental cells, the mRNA expression levels of IGF-1 R, extracellular-signal-regulated kinase 1 (ERK 1), AKT 1, and EGFR in A549/GR cells are elevated (p<0.05), which were associated with reduced apoptotic capacity.Conclusions Both IGF-1/PI3K and IGF-1/ERK signaling pathways are activated in gefitinib-resistant non-small cell lung cancer cells with the wild-type EGFR.