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- W2491898702 abstract "EGFR is one of key driver pathways of non-small cell lung cancer (NSCLC). EGFR inhibitors have shown significant response in patients with EGFR mutation. However, patients develop resistance in short period of time, which results from secondary EGFRT790M mutation and other mechanisms. Here, we demonstrated that activating mutations of EGFR significantly activated IKBKE, an IκB kinase family member previously shown to activate Akt and NF-κB pathways. Furthermore, we showed that EGFR directly interacts with and phosphorylates IKBKE on tyrosine 153 and tyrosine 179 residues. IKBKE-Y153F/179-F, a mutant that could not be phosphorylated by EGFR, largely reduced its kinase activity and failed to activate Akt and NF-κB as well as inhibited EGFR signaling. Furthermore, phospho-IKBKE-Y153 correlated with EGFR activation in NSCLC patients. Notably, depletion of IKBKE by either small molecule inhibitor amlexanox or shRNA selectively inhibited cell viability in NSCLC cells with EGFR mutations. Moreover, we observed that inhibition of IKBKE led to feedback activation of the MAPK pathway. Combination of amlexanox with MEK inhibitor AZD6244 significantly inhibits cell survival and tumor growth in NSCLC cells driven by activating EGFR mutations including EGFRT790M. Thus, our findings not only identify IKBKE as a direct downstream target of EGFR but also provide a potential therapeutic strategy for EGFR-TKI resistant NSCLC driven by secondary EGFR mutation. Citation Format: Sridevi Challa, Jian-Ping Guo, Cheng-xiong Xu, Yajuan Li, Donghwa Kim, Douglas Cress, Eric Haura, Domenico Coppola, Jin Cheng. IKBKE is a substrate of EGFR and a therapeutic target in NSCLCs with activating mutations of EGFR. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1890." @default.
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- W2491898702 date "2016-07-15" @default.
- W2491898702 modified "2023-09-23" @default.
- W2491898702 title "Abstract 1890: IKBKE is a substrate of EGFR and a therapeutic target in NSCLCs with activating mutations of EGFR" @default.
- W2491898702 doi "https://doi.org/10.1158/1538-7445.am2016-1890" @default.
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