Abstract 964: Gefitinib resistance due to STAT3-mediated Akt activation in lung cancer cells.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs), including gefitinib and erlotinib, are effective drugs for a subset of non-small cell lung cancer. Gefitinib binds to the tyrosine kinase domain of EGFR and hence inactivates its downstream prosurvival signaling pathways, including PI3k/Akt and MAPK pathways. However, most patients received gefitinib eventually developed resistance to this drug. In this study, we demonstrated that in gefitinib-treated A549 cells (human lung cancer cell line), Akt activation undergoes a time-dependent recovery following an initial inhibition by gefitinib. Since constant activation of Akt has been associated with treatment failure of gefitinib in lung cancer cells, exploring the mechanisms that lead to Akt restoration should provide new insights into the drug resistance and therapeutic efficacy. For that purpose, alterations in Akt activation and other signaling pathways, including MAPK and STAT3, involved in EGFR-mediated cellular responses were determined in A549 cells treated with gefitinib. Among them, we found that activation of STAT3 was inhibited in the cells without gefitinib treatment. Gefitinib treatment inhibited EGFR phosphorylation on tyrosine 1086 (Y1086), which leads to STAT3 activation. Further studies showed that interruption of the STAT3 signaling by either chemical inhibitor or siRNA against STAT3 prevented fast recovery of Akt activation and enhanced gefitinib-induced suppression of cell proliferation. Taken together, these data suggest that activation of STAT3 is an intrinsic mechanism of drug resistance in response to EGFR TKIs. Combinational targeting on both EGFR and STAT3 may enhance the efficacy of gefitinib or other EGFR TKIs on lung cancer. Citation Format: Kai Wu, Yongju Lu, Bailing Chen, Qingshan Chang, Ping Qiu, Miaomiao Yu. Gefitinib resistance due to STAT3-mediated Akt activation in lung cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 964. doi:10.1158/1538-7445.AM2013-964