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

Jung Min Choi, Ji Young Jang, Yu Ra Choi, Hye Ryun Kim, ByoungChul Cho, Han Woong Lee

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)175-181
Number of pages7
JournalLung Cancer
Volume90
Issue number2
DOIs
Publication statusPublished - 2015 Aug 2

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Growth Factor Receptors
Protein-Tyrosine Kinases
Lung Neoplasms
Insulin
Receptor Protein-Tyrosine Kinases
Drug Resistance
Neoplasms
Clone Cells
Drug and Narcotic Control
p53 Genes
Insulin-Like Growth Factor I
Epidermal Growth Factor Receptor
Protein Kinases
Phosphotransferases
Therapeutics
Biomarkers
Cell Line
Messenger RNA
Survival
Mortality

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Cite this

Choi, Jung Min ; Jang, Ji Young ; Choi, Yu Ra ; Kim, Hye Ryun ; Cho, ByoungChul ; Lee, Han Woong. / Reduced expression of EI24 confers resistance to gefitinib through IGF-1R signaling in PC9 NSCLC cells. In: Lung Cancer. 2015 ; Vol. 90, No. 2. pp. 175-181.
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title = "Reduced expression of EI24 confers resistance to gefitinib through IGF-1R signaling in PC9 NSCLC cells",
abstract = "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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Reduced expression of EI24 confers resistance to gefitinib through IGF-1R signaling in PC9 NSCLC cells. / Choi, Jung Min; Jang, Ji Young; Choi, Yu Ra; Kim, Hye Ryun; Cho, ByoungChul; Lee, Han Woong.

In: Lung Cancer, Vol. 90, No. 2, 02.08.2015, p. 175-181.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Reduced expression of EI24 confers resistance to gefitinib through IGF-1R signaling in PC9 NSCLC cells

AU - Choi, Jung Min

AU - Jang, Ji Young

AU - Choi, Yu Ra

AU - Kim, Hye Ryun

AU - Cho, ByoungChul

AU - Lee, Han Woong

PY - 2015/8/2

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N2 - 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.

AB - 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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