FBXW 7 deletion contributes to lung tumor development and confers resistance to gefitinib therapy
Abstract
Gefitinib, an epidermal growth factor receptor–tyrosine kinase inhibitor ( EGFR ‐ TKI ), is an effective treatment for non‐small‐cell lung cancer ( NSCLC ) with EGFR activating mutations, but inevitably, the clinical efficacy is impeded by the emergence of acquired resistance. The tumor suppressor gene FBXW 7 modulates chemosensitivity in various human cancers. However, its role in EGFR ‐ TKI therapy in NSCLC has not been well studied. Here, we demonstrate that the mice with deficient Fbxw7 have greater susceptibility to urethane‐induced lung tumor development. Through analysis of The Cancer Genome Atlas data, we show that deletion of FBXW 7 occurs in 30.9% of lung adenocarcinomas and 63.5% of lung squamous cell carcinomas, which significantly leads to decrease in FBXW 7 mRNA expression. The reduction in FBXW 7 mRNA level is associated with poor overall survival in lung cancer patients. FBXW 7 knockdown dramatically promotes epithelial–mesenchymal transition, migration, and invasion in NSCLC cells. Moreover, with silenced FBXW 7, EGFR ‐ TKI ‐sensitive cells become resistant to gefitinib, which is reversed by the mammalian target of rapamycin inhibitor, rapamycin. Furthermore, xenograft mouse model studies show that FBXW 7 knockdown enhances tumorigenesis and resistance to gefitinib. Combination of gefitinib with rapamycin treatment suppressesmore »
- Authors:
-
- Department of Biochemistry and Molecular Biology Shandong University School of Basic Medical Sciences Jinan China
- Department of Clinical Laboratory The Second Hospital of Shandong University Jinan China
- Biological Systems and Engineering Division Lawrence Berkeley National Laboratory CA USA
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC) Instituto Mixto Universidad de Salamanca/CSIC IBSAL Salamanca Spain
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE; Natural Science Foundation of Shandong Province; National Natural Science Foundation of China (NSFC); FEDER; MICINN; Instituto de Salud Carlos III; ‘We can be heroes’ Foundation
- OSTI Identifier:
- 1436552
- Alternate Identifier(s):
- OSTI ID: 1436557; OSTI ID: 1623436
- Grant/Contract Number:
- AC02-05CH11231; ZR2014HM032; 81470127; 81672858; SAF2014‐56989‐R; SAF2017‐88854R; PIE14/00066
- Resource Type:
- Published Article
- Journal Name:
- Moletular Oncology
- Additional Journal Information:
- Journal Name: Moletular Oncology Journal Volume: 12 Journal Issue: 6; Journal ID: ISSN 1574-7891
- Publisher:
- Wiley Blackwell (John Wiley & Sons)
- Country of Publication:
- Netherlands
- Language:
- English
- Subject:
- Oncology
Citation Formats
Xiao, Yi, Yin, Chunli, Wang, Yuli, Lv, Hanlin, Wang, Wenqing, Huang, Yurong, Perez‐Losada, Jesus, Snijders, Antoine M., Mao, Jian‐Hua, and Zhang, Pengju. FBXW 7 deletion contributes to lung tumor development and confers resistance to gefitinib therapy. Netherlands: N. p., 2018.
Web. doi:10.1002/1878-0261.12200.
Xiao, Yi, Yin, Chunli, Wang, Yuli, Lv, Hanlin, Wang, Wenqing, Huang, Yurong, Perez‐Losada, Jesus, Snijders, Antoine M., Mao, Jian‐Hua, & Zhang, Pengju. FBXW 7 deletion contributes to lung tumor development and confers resistance to gefitinib therapy. Netherlands. https://doi.org/10.1002/1878-0261.12200
Xiao, Yi, Yin, Chunli, Wang, Yuli, Lv, Hanlin, Wang, Wenqing, Huang, Yurong, Perez‐Losada, Jesus, Snijders, Antoine M., Mao, Jian‐Hua, and Zhang, Pengju. Wed .
"FBXW 7 deletion contributes to lung tumor development and confers resistance to gefitinib therapy". Netherlands. https://doi.org/10.1002/1878-0261.12200.
@article{osti_1436552,
title = {FBXW 7 deletion contributes to lung tumor development and confers resistance to gefitinib therapy},
author = {Xiao, Yi and Yin, Chunli and Wang, Yuli and Lv, Hanlin and Wang, Wenqing and Huang, Yurong and Perez‐Losada, Jesus and Snijders, Antoine M. and Mao, Jian‐Hua and Zhang, Pengju},
abstractNote = {Gefitinib, an epidermal growth factor receptor–tyrosine kinase inhibitor ( EGFR ‐ TKI ), is an effective treatment for non‐small‐cell lung cancer ( NSCLC ) with EGFR activating mutations, but inevitably, the clinical efficacy is impeded by the emergence of acquired resistance. The tumor suppressor gene FBXW 7 modulates chemosensitivity in various human cancers. However, its role in EGFR ‐ TKI therapy in NSCLC has not been well studied. Here, we demonstrate that the mice with deficient Fbxw7 have greater susceptibility to urethane‐induced lung tumor development. Through analysis of The Cancer Genome Atlas data, we show that deletion of FBXW 7 occurs in 30.9% of lung adenocarcinomas and 63.5% of lung squamous cell carcinomas, which significantly leads to decrease in FBXW 7 mRNA expression. The reduction in FBXW 7 mRNA level is associated with poor overall survival in lung cancer patients. FBXW 7 knockdown dramatically promotes epithelial–mesenchymal transition, migration, and invasion in NSCLC cells. Moreover, with silenced FBXW 7, EGFR ‐ TKI ‐sensitive cells become resistant to gefitinib, which is reversed by the mammalian target of rapamycin inhibitor, rapamycin. Furthermore, xenograft mouse model studies show that FBXW 7 knockdown enhances tumorigenesis and resistance to gefitinib. Combination of gefitinib with rapamycin treatment suppresses tumor formation of gefitinib‐resistant (GR) FBXW 7‐knockdown cells. In conclusion, our findings suggest that loss of FBXW 7 promotes NSCLC progression as well as gefitinib resistance and combination of gefitinib and rapamycin may provide an effective therapy for GR NSCLC.},
doi = {10.1002/1878-0261.12200},
journal = {Moletular Oncology},
number = 6,
volume = 12,
place = {Netherlands},
year = {Wed May 09 00:00:00 EDT 2018},
month = {Wed May 09 00:00:00 EDT 2018}
}
https://doi.org/10.1002/1878-0261.12200
Web of Science
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