Document Detail


Increased VEGFR-2 gene copy is associated with chemoresistance and shorter survival in patients with non-small-cell lung carcinoma who receive adjuvant chemotherapy.
MedLine Citation:
PMID:  21724587     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
VEGF receptor-2 (VEGFR-2 or kinase insert domain receptor; KDR) is a known endothelial target also expressed in NSCLC tumor cells. We investigated the association between alterations in the KDR gene and clinical outcome in patients with resected non-small-cell lung carcinoma (NSCLC; n = 248). KDR copy number gains (CNG), measured by quantitative PCR and fluorescence in situ hybridization, were detected in 32% of tumors and associated with significantly higher KDR protein and higher microvessel density than tumors without CNGs. KDR CNGs were also associated with significantly increased risk of death (HR = 5.16; P = 0.003) in patients receiving adjuvant platinum-based chemotherapy, but no differences were observed in patients not receiving adjuvant therapy. To investigate potential mechanisms for these associations, we assessed NSCLC cell lines and found that KDR CNGs were significantly associated with in vitro resistance to platinum chemotherapy as well as increased levels of nuclear hypoxia inducible factor-1α (HIF-1α) in both NSCLC tumor specimens and cell lines. Furthermore, KDR knockdown experiments using small interfering RNA reduced platinum resistance, cell migration, and HIF-1α levels in cells bearing KDR CNGs, providing evidence for direct involvement of KDR. No KDR mutations were detected in exons 7, 11, and 21 by PCR-based sequencing; however, two variant single nucleotide polymorphism genotypes were associated with favorable overall survival in adenocarcinoma patients. Our findings suggest that tumor cell KDR CNGs may promote a more malignant phenotype including increased chemoresistance, angiogenesis, and HIF-1α levels, and that KDR CNGs may be a useful biomarker for identifying patients at high risk for recurrence after adjuvant therapy, a group that may benefit from VEGFR-2 blockade.
Authors:
Fei Yang; Ximing Tang; Erick Riquelme; Carmen Behrens; Monique B Nilsson; Uma Giri; Marileila Varella-Garcia; Lauren A Byers; Heather Y Lin; Jing Wang; Maria G Raso; Luc Girard; Kevin Coombes; J Jack Lee; Roy S Herbst; John D Minna; John V Heymach; Ignacio I Wistuba
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2011-07-01
Journal Detail:
Title:  Cancer research     Volume:  71     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-08-15     Completed Date:  2011-10-13     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5512-21     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Carcinoma, Non-Small-Cell Lung / drug therapy*,  genetics
Chemotherapy, Adjuvant*
Drug Resistance, Neoplasm
Gene Dosage*
Humans
In Situ Hybridization, Fluorescence
Lung Neoplasms / drug therapy*,  genetics
Polymerase Chain Reaction
Polymorphism, Single Nucleotide
Survival Rate
Vascular Endothelial Growth Factor Receptor-2 / genetics*
Grant Support
ID/Acronym/Agency:
CA-16672/CA/NCI NIH HHS; P30 CA016672-34/CA/NCI NIH HHS; P50 CA058187/CA/NCI NIH HHS; P50 CA058187-16/CA/NCI NIH HHS; P50 CA070907/CA/NCI NIH HHS; P50 CA070907-15/CA/NCI NIH HHS; P50CA58187/CA/NCI NIH HHS; P50CA70907/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
EC 2.7.10.1/Vascular Endothelial Growth Factor Receptor-2
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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