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Title: 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 » 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.« less

Authors:
 [1];  [1];  [2];  [1];  [1];  [3];  [4];  [3];  [3];  [1]
  1. Department of Biochemistry and Molecular Biology Shandong University School of Basic Medical Sciences Jinan China
  2. Department of Clinical Laboratory The Second Hospital of Shandong University Jinan China
  3. Biological Systems and Engineering Division Lawrence Berkeley National Laboratory CA USA
  4. 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}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1002/1878-0261.12200

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Works referenced in this record:

Online Survival Analysis Software to Assess the Prognostic Value of Biomarkers Using Transcriptomic Data in Non-Small-Cell Lung Cancer
journal, December 2013


Snail and Slug Mediate Radioresistance and Chemoresistance by Antagonizing p53-Mediated Apoptosis and Acquiring a Stem-Like Phenotype in Ovarian Cancer Cells
journal, September 2009

  • Kurrey, Nawneet K.; Jalgaonkar, Swati P.; Joglekar, Alok V.
  • Stem Cells, Vol. 27, Issue 9
  • DOI: 10.1002/stem.154

Inactivation of hCDC4 can cause chromosomal instability
journal, March 2004

  • Rajagopalan, Harith; Jallepalli, Prasad V.; Rago, Carlo
  • Nature, Vol. 428, Issue 6978
  • DOI: 10.1038/nature02313

FBXW7 Targets mTOR for Degradation and Cooperates with PTEN in Tumor Suppression
journal, September 2008


Effects of oncogenic mutations on the conformational free-energy landscape of EGFR kinase
journal, June 2013

  • Sutto, L.; Gervasio, F. L.
  • Proceedings of the National Academy of Sciences, Vol. 110, Issue 26
  • DOI: 10.1073/pnas.1221953110

A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice
journal, July 2006

  • To, Minh D.; Perez-Losada, Jesus; Mao, Jian-Hua
  • Nature Genetics, Vol. 38, Issue 8
  • DOI: 10.1038/ng1836

Epithelial–mesenchymal transition with expression of SNAI1-induced chemoresistance in colorectal cancer
journal, December 2009

  • Hoshino, Hiromitsu; Miyoshi, Norikatsu; Nagai, Ken-ichi
  • Biochemical and Biophysical Research Communications, Vol. 390, Issue 3
  • DOI: 10.1016/j.bbrc.2009.10.117

Role of KRAS and EGFR As Biomarkers of Response to Erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21
journal, September 2008

  • Zhu, Chang-Qi; da Cunha Santos, Gilda; Ding, Keyue
  • Journal of Clinical Oncology, Vol. 26, Issue 26
  • DOI: 10.1200/JCO.2007.14.8924

The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP
journal, January 2008

  • Yun, C. -H.; Mengwasser, K. E.; Toms, A. V.
  • Proceedings of the National Academy of Sciences, Vol. 105, Issue 6
  • DOI: 10.1073/pnas.0709662105

Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer
journal, October 2006

  • Engelman, J. A.; Mukohara, T.; Zejnullahu, K.
  • Journal of Clinical Investigation, Vol. 116, Issue 10
  • DOI: 10.1172/JCI28656

Erlotinib in Previously Treated Non–Small-Cell Lung Cancer
journal, July 2005

  • Shepherd, Frances A.; Rodrigues Pereira, José; Ciuleanu, Tudor
  • New England Journal of Medicine, Vol. 353, Issue 2
  • DOI: 10.1056/NEJMoa050753

Clinical implications of T790M mutation in patients with acquired resistance to EGFR tyrosine kinase inhibitors
journal, November 2013


Non-Small Cell Lung Cancer: Epidemiology, Risk Factors, Treatment, and Survivorship
journal, May 2008


Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLC
journal, September 2013


FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR
journal, March 2011

  • Bivona, Trever G.; Hieronymus, Haley; Parker, Joel
  • Nature, Vol. 471, Issue 7339
  • DOI: 10.1038/nature09870

FBXW7/hCDC4 Is a General Tumor Suppressor in Human Cancer
journal, October 2007


Novel mutant-selective EGFR kinase inhibitors against EGFR T790M
journal, December 2009

  • Zhou, Wenjun; Ercan, Dalia; Chen, Liang
  • Nature, Vol. 462, Issue 7276
  • DOI: 10.1038/nature08622

Baseline Gene Expression Predicts Sensitivity to Gefitinib in Non-Small Cell Lung Cancer Cell Lines
journal, August 2006


Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene
journal, December 2004

  • Mao, Jian-Hua; Perez-losada, Jesus; Wu, Di
  • Nature, Vol. 432, Issue 7018
  • DOI: 10.1038/nature03155

mTOR Inhibitors Control the Growth of EGFR Mutant Lung Cancer Even after Acquiring Resistance by HGF
journal, May 2013


Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7
journal, March 2011

  • Wertz, Ingrid E.; Kusam, Saritha; Lam, Cynthia
  • Nature, Vol. 471, Issue 7336
  • DOI: 10.1038/nature09779

Clinical Features and Outcome of Patients With Non–Small-Cell Lung Cancer Who Harbor EML4-ALK
journal, September 2009

  • Shaw, Alice T.; Yeap, Beow Y.; Mino-Kenudson, Mari
  • Journal of Clinical Oncology, Vol. 27, Issue 26
  • DOI: 10.1200/JCO.2009.22.6993

Preexistence and Clonal Selection of MET Amplification in EGFR Mutant NSCLC
journal, January 2010


Mouse Fbw7/Sel-10/Cdc4 Is Required for Notch Degradation during Vascular Development
journal, December 2003

  • Tsunematsu, Ryosuke; Nakayama, Keiko; Oike, Yuichi
  • Journal of Biological Chemistry, Vol. 279, Issue 10
  • DOI: 10.1074/jbc.M312337200

Temsirolimus therapy in a patient with lung adenocarcinoma harboring an FBXW7 mutation
journal, February 2014


Allele-Specific Deletions in Mouse Tumors Identify Fbxw7 as Germline Modifier of Tumor Susceptibility
journal, February 2012


Upstream and downstream of mTOR
journal, August 2004


AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer
journal, June 2014


Immunohistochemical α- and β-catenin and E-cadherin expression and their clinicopathological significance in human lung adenocarcinoma
journal, September 2006

  • Nozawa, Nobuyoshi; Hashimoto, Shuichi; Nakashima, Yutaka
  • Pathology - Research and Practice, Vol. 202, Issue 9
  • DOI: 10.1016/j.prp.2006.03.007

Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors
journal, March 2011


FBXW7 Mediates Chemotherapeutic Sensitivity and Prognosis in NSCLCs
journal, October 2013


Mcl-1 and FBW7 Control a Dominant Survival Pathway Underlying HDAC and Bcl-2 Inhibitor Synergy in Squamous Cell Carcinoma
journal, December 2012


Expression profiling of epithelial plasticity in tumor progression
journal, October 2003


Gefitinib (Iressa®): a novel treatment for non-small cell lung cancer
journal, February 2004


Cancer statistics, 2017
journal, January 2017

  • Siegel, Rebecca L.; Miller, Kimberly D.; Jemal, Ahmedin
  • CA: A Cancer Journal for Clinicians, Vol. 67, Issue 1
  • DOI: 10.3322/caac.21387

Noncovalent Wild-type–Sparing Inhibitors of EGFR T790M
journal, December 2012


Role of the ubiquitin ligase Fbw7 in cancer progression
journal, November 2011


FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation
journal, February 2008

  • Welcker, Markus; Clurman, Bruce E.
  • Nature Reviews Cancer, Vol. 8, Issue 2
  • DOI: 10.1038/nrc2290

Molecular histology of lung cancer: From targets to treatments
journal, April 2015

  • Wood, Steven L.; Pernemalm, Maria; Crosbie, Philip A.
  • Cancer Treatment Reviews, Vol. 41, Issue 4
  • DOI: 10.1016/j.ctrv.2015.02.008

FBW7 Upregulation Enhances Cisplatin Cytotoxicity in Non-small Cell Lung Cancer Cells
journal, November 2013