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ABCG2 is a potential biomarker causing multidrug resistance (MDR) in Non-Small Cell Lung Cancer (NSCLC).We conducted this study to investigate whether Icotinib,a small-molecule inhibitor of EGFR tyrosine kinase, could interact with ABCG2 transporter in NSCLC.Our results showed that Icotinib reversed ABCG2-mediated MDR by antagonizing the drug effiux function of ABCG2.Icotinib stimulated the ATPase activity in a concentration-dependent manner and inhibited the photolabeling of ABCG2 with [125I]-Iodoarylazidoprazosin, demonstrating that it interacts at the drug-binding pocket.Homology modeling predicted the binding conformation of Icotinib at Asn629 centroid-based grid of ABCG2.However, Icotinib at reversal concentration did not affect the expression levels of AKT and ABCG2.Furthermore, a combination of Icotinib and topotecan exhibited significant synergistic anticancer activity against NCI-H460/MX20 tumor xenografts.However, the inhibition of transport activity of ABCG2 was insufficient to overcome pemetrexed resistance in NCI-H460/MX20 cells, which was due to the co-upregulated thymidylate synthase (TS) and ABCG2 expression.This is the first report to show that the up-regulation of TS in ABCG2-overexpressing cell line NCI-H460/MX20 may play a role of resistance to pemetrexate.Our findings suggested different possible strategies of overcoming the resistance oftopotecan and pemetrexed in the NSCLC patients.