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Reduced expression of EI24 confers resistance to gefitinib through IGF-1R signaling in PC9 NSCLC cells

 Jung-Min Choi  ;  Ji-Young Jang  ;  Han-Woong Lee  ;  Byoung Chul Cho  ;  Hye Ryun Kim  ;  Yu-Ra Choi 
 LUNG CANCER, Vol.90(2) : 175-181, 2015 
Journal Title
Issue Date
Antineoplastic Agents/pharmacology ; Apoptosis Regulatory Proteins/genetics* ; Carcinoma, Non-Small-Cell Lung/drug therapy* ; Carcinoma, Non-Small-Cell Lung/genetics* ; Cell Line, Tumor ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/genetics ; Humans ; Insulin/genetics ; Lung Neoplasms/drug therapy* ; Lung Neoplasms/genetics* ; Mutation/drug effects ; Mutation/genetics ; Nuclear Proteins/genetics* ; Protein Kinase Inhibitors/pharmacology ; Protein-Tyrosine Kinases/genetics ; Quinazolines/pharmacology* ; RNA, Messenger/genetics ; Receptor, Epidermal Growth Factor/genetics ; Receptor, IGF Type 1/genetics* ; Signal Transduction/drug effects
Drug resistance ; EGFR-TKI ; EI24 ; IGF-1R ; NSCLC
OBJECTIVES: Lung cancer is the commonly diagnosed cancer and is the leading cause of cancer-related mortality worldwide. The most prevalent form of lung cancer is NSCLC, comprising 80% of all lung cancer cases, and epidermal growth factor receptor (EGFR) is frequently mutated in NSCLC. EI24 is a p53-responsive gene and plays an important role in tumor suppression. In the current study, we found that reduced expression of EI24 conferred resistance to EGFR-tyrosine-kinase inhibitor (TKI) in NSCLC cells. MATERIALS AND METHODS: The correlation between EI24 expression and EGFR-TKI drug resistance in EGFR-driven tumors were determined from microarray datasets. The phospho-protein expression profiles of receptor tyrosine kinases and protein kinases were examined using antibody arrays method in PC9 cells expressing shRNAs targeting EI24 and gefitinib-resistant PC9-GR cells expressing exogenous EI24. RESULTS AND CONCLUSIONS: The EGFR-TKI resistant clones had reduced expression of EI24 mRNA compared to the sensitive clones, and EI24 knockdown rendered sensitive cells resistant to EGFR-TKI. Receptor tyrosine kinase screening revealed the involvement of a kinase switch in EI24-mediated regulation of drug sensitivity. We found that EI24 modulates the insulin growth factor-1 receptor (IGF-1R) pathway through the induction of IGF-1. Combination treatment with EGFR and IGF-1R inhibitors significantly reduced the viability of EI24 knockdown-induced resistant cell lines compared to single-agent treatments. We also showed that low EI24 and high IGF-1R expressions in lung cancer patients were correlated with reduced overall survival. Taken together, these results suggest a potential role for EI24 as a biomarker of drug resistance, and indicate that combination therapy with EGFR and IGF-1R inhibitors would be effective in NSCLC patients with low EI24 expression.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hye Ryun(김혜련) ORCID logo https://orcid.org/0000-0002-1842-9070
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
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