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Wang DS , Patel A , Shukla S , Zhang YK , Wang YJ , Kathawala RJ , Robey RW , Zhang L , Yang DH , Talele TT , Bates SE , Ambudkar SV , Xu RH , Chen ZS
Icotinib antagonizes ABCG2-mediated multidrug resistance, but not the pemetrexed resistance mediated by thymidylate synthase and ABCG2
Oncotarget. 2014 Jun 30;5(12) :4529-42
PMID: 24980828    PMCID: PMC4147343   
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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 efflux 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 of topotecan and pemetrexed in the NSCLC patients.
1949-2553 Wang, De-Shen Patel, Atish Shukla, Suneet Zhang, Yun-Kai Wang, Yi-Jun Kathawala, Rishil J Robey, Robert W Zhang, Li Yang, Dong-Hua Talele, Tanaji T Bates, Susan E Ambudkar, Suresh V Xu, Rui-Hua Chen, Zhe-Sheng Journal Article United States Oncotarget. 2014 Jun 30;5(12):4529-42.