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


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.


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.
Department of Biochemistry, College of Life Science and Biotechnology, Seoul, South Korea.
Jung-Min
JM
Choi
Department of Biochemistry, College of Life Science and Biotechnology, Seoul, South Korea.
Ji-Young
JY
Jang
Department of Biochemistry, College of Life Science and Biotechnology, Seoul, South Korea.
Yu-Ra
YR
Choi
Yonsei Cancer Center, Division of Medical Oncology, Yonsei University College of Medicine, Seoul, South Korea; Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
Hye Ryun
HR
Kim
Yonsei Cancer Center, Division of Medical Oncology, Yonsei University College of Medicine, Seoul, South Korea; Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
Byoung Chul
BC
Cho
Department of Biochemistry, College of Life Science and Biotechnology, Seoul, South Korea; Laboratory Animal Research Center, Yonsei University, Seoul, South Korea. Electronic address: hwl@yonsei.ac.kr.
Han-Woong
HW
Lee
D000970:Antineoplastic Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D000077156:Gefitinib; D006801:Humans; D007328:Insulin / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C402592:EI24 protein, human; D007328:Insulin; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D000077156:Gefitinib
Drug resistance; EGFR-TKI; EI24; IGF-1R; NSCLC