skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: FBXW 7 deletion contributes to lung tumor development and confers resistance to gefitinib therapy

Journal Article · · Moletular Oncology
 [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
+ Show Author Affiliations

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.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
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
Grant/Contract Number:
AC02-05CH11231; ZR2014HM032; 81470127; 81672858; SAF2014‐56989‐R; SAF2017‐88854R; PIE14/00066
OSTI ID:
1436552
Alternate ID(s):
OSTI ID: 1436557; OSTI ID: 1623436
Journal Information:
Moletular Oncology, Journal Name: Moletular Oncology Vol. 12 Journal Issue: 6; ISSN 1574-7891
Publisher:
Wiley Blackwell (John Wiley & Sons)Copyright Statement
Country of Publication:
Netherlands
Language:
English
Citation Metrics:
Cited by: 24 works
Citation information provided by
Web of Science

References (47)

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
Inactivation of hCDC4 can cause chromosomal instability journal March 2004
FBXW7 Targets mTOR for Degradation and Cooperates with PTEN in Tumor Suppression journal September 2008
The search for improved systemic therapy of non-small cell lung cancer—What are today's options? journal June 2011
Effects of oncogenic mutations on the conformational free-energy landscape of EGFR kinase journal June 2013
A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice journal July 2006
Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors journal August 2009
Epithelial–mesenchymal transition with expression of SNAI1-induced chemoresistance in colorectal cancer journal December 2009
Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial journal February 2010
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
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial journal March 2012
The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP journal January 2008
Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer journal October 2006
Erlotinib in Previously Treated Non–Small-Cell Lung Cancer journal July 2005
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
Targeting mTOR to Overcome Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance in Non-Small Cell Lung Cancer Cells journal July 2013
FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR journal March 2011
Loss of Activating EGFR Mutant Gene Contributes to Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in Lung Cancer Cells journal July 2012
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
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
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
Biomarker Analyses and Final Overall Survival Results From a Phase III, Randomized, Open-Label, First-Line Study of Gefitinib Versus Carboplatin/Paclitaxel in Clinically Selected Patients With Advanced Non–Small-Cell Lung Cancer in Asia (IPASS) journal July 2011
Clinical Features and Outcome of Patients With Non–Small-Cell Lung Cancer Who Harbor EML4-ALK journal September 2009
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
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
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
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
Molecular histology of lung cancer: From targets to treatments journal April 2015
FBW7 Upregulation Enhances Cisplatin Cytotoxicity in Non-small Cell Lung Cancer Cells journal November 2013

Similar Records

MiR-181a contributes gefitinib resistance in non-small cell lung cancer cells by targeting GAS7
Journal Article · Mon Jan 15 00:00:00 EST 2018 · Biochemical and Biophysical Research Communications · OSTI ID:1436552
+3 more
Short-Course Treatment With Gefitinib Enhances Curative Potential of Radiation Therapy in a Mouse Model of Human Non-Small Cell Lung Cancer
Journal Article · Sat Mar 15 00:00:00 EDT 2014 · International Journal of Radiation Oncology, Biology and Physics · OSTI ID:1436552
+1 more
Potential influence of interleukin-6 on the therapeutic effect of gefitinib in patients with advanced non-small cell lung cancer harbouring EGFR mutations
Journal Article · Mon Jan 15 00:00:00 EST 2018 · Biochemical and Biophysical Research Communications · OSTI ID:1436552
+3 more

Related Subjects

Oncology