IKBKE Is a Substrate of EGFR and a Therapeutic Target in Non-Small Cell Lung Cancer with Activating Mutations of EGFR.
Non-small cell lung cancers (NSCLC) marked by EGFR mutations tend to develop resistance to therapeutic EGFR inhibitors, often due to secondary mutation EGFR(T790M) but also other mechanisms. Here we report support for a rationale to target IKBKE, an IκB kinase family member that activates the AKT and NF-κB pathways, as one strategy to address NSCLC resistant to EGFR inhibitors. While wild-type and mutant EGFR directly interacted with IKBKE, only mutant EGFR phosphorylated IKBKE on residues Y153 and Y179. The unphosphorylatable mutant IKBKE-Y153F/Y179-F that lost kinase activity failed to activate AKT and inhibited EGFR signaling. In clinical specimens of NSCLC with activating mutations of EGFR, we observed elevated levels of phospho-Y153 IKBKE. IKBKE ablation with shRNA or small-molecule inhibitor amlexanox selectively inhibited the viability of NSCLC cells with EGFR mutations in vitro In parallel, we found that these treatments activated the MAPK pathway due to attenuation of an IKBKE feedback mechanism. In vivo studies revealed that combining amlexanox with MEK inhibitor AZD6244 significantly inhibited the xenograft tumor growth of NSCLC cells harboring activating EGFR mutations, including EGFR(T790M) Overall, our findings define IKBKE as a direct effector target of EGFR and provide a therapeutic rationale to target IKBKE as a strategy to eradicate EGFR-TKI-resistant NSCLC cells. Cancer Res; 76(15); 4418-29. ©2016 AACR.
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Sridevi
S
Challa
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Jian-Ping
JP
Guo
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Xiaowen
X
Ding
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Cheng-Xiong
CX
Xu
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Yajuan
Y
Li
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Donghwa
D
Kim
Thoracic Oncology and Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
Matthew A
MA
Smith
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Douglas W
DW
Cress
Department of Anatomic Pathology and Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Domenico
D
Coppola
Thoracic Oncology and Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
Eric B
EB
Haura
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. jin.cheng@moffitt.org.
Jin Q
JQ
Cheng
D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D014162:Transfection
D066246:ErbB Receptors; D051550:I-kappa B Kinase; C496565:IKBKE protein, human