期刊
EUROPEAN JOURNAL OF CANCER
卷 49, 期 16, 页码 3559-3572出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2013.07.007
关键词
Notch-1; Epithelial-mesenchymal transition; EGFR-TKI; Drug resistance
类别
资金
- Natural Science Foundation of Guangdong Province [S2012010008591]
- Cancer target therapy research fund of Wu Jieping Medial Foundation [320.6720.10015]
- Open Funds of State Key Laboratory of Oncology in Southern China [HN2013-06]
- Translational Research Foundation of the First Affiliated Hospital of Guangzhou Medical University [201206-gyfyy]
Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) occurs in non-small cell lung cancer (NSCLC) patients who initially respond to TKI treatment but whose cancer then progresses. Recent studies have shown that Notch signal is associated with drug resistance. However, the exact mechanism of Notch during acquisition of resistance to EGFR-TKI in human lung cancer remains unclear. In the present study, we showed that the expression of Notch-1 was highly upregulated in EGFR-TKI acquired resistant lung cancer cells. More importantly, Notch-1 contributed to the acquisition of the epithelial-mesenchymal transition (EMT) phenotype, which was critically associated with acquired resistance to EGFR-TKI. Silencing of Notch-1 using siRNA resulted in mesenchymal-epithelial transition (MET), which was associated with impaired invasion and anchorage-independent growth of lung cancer and resensitisation to gefitinib in acquired resistant NSCLC cells. Finally, gefitinib treatment of Balb/c nu/nu with acquired resistant lung cancer xenografts in combination with Notch inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester (DAPT) resulted in effective tumour growth retardation, with decreased proliferative activity and increased apoptotic activity. Collectively, these data suggest that Notch-1 might play a novel role in acquired resistance to gefitinib, which could be reversed by inhibiting Notch-1. Crown Copyright (C) 2013 Published by Elsevier Ltd. All rights reserved.
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