Increased VEGFR-2 gene copy is associated with chemoresistance and shorter survival in patients with non-small-cell lung carcinoma who receive adjuvant chemotherapy

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

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

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-1a 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.

Original languageEnglish (US)
Pages (from-to)5512-5521
Number of pages10
JournalCancer Research
Volume71
Issue number16
DOIs
StatePublished - Aug 15 2011

Fingerprint

Vascular Endothelial Growth Factor Receptor-2
Adjuvant Chemotherapy
Non-Small Cell Lung Carcinoma
Platinum
Survival
Hypoxia-Inducible Factor 1
Genes
Neoplasms
Drug Therapy
Polymerase Chain Reaction
Vascular Endothelial Growth Factor Receptor
Group Psychotherapy
Microvessels
Tumor Cell Line
Fluorescence In Situ Hybridization
Small Interfering RNA
Cell Movement
Single Nucleotide Polymorphism
Exons
Adenocarcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Increased VEGFR-2 gene copy is associated with chemoresistance and shorter survival in patients with non-small-cell lung carcinoma who receive adjuvant chemotherapy. / Yang, Fei; Tang, Ximing; Riquelme, Erick; Behrens, Carmen; Nilsson, Monique B.; Giri, Uma; Varella-Garcia, Marileila; Byers, Lauren A.; Lin, Heather Y.; Wang, Jing; Raso, Maria G.; Girard, Luc; Coombes, Kevin; Lee, J. Jack; Herbst, Roy S.; Minna, John D.; Heymach, John V.; Wistuba, Ignacio I.

In: Cancer Research, Vol. 71, No. 16, 15.08.2011, p. 5512-5521.

Research output: Contribution to journalArticle

Yang, F, Tang, X, Riquelme, E, Behrens, C, Nilsson, MB, Giri, U, Varella-Garcia, M, Byers, LA, Lin, HY, Wang, J, Raso, MG, Girard, L, Coombes, K, Lee, JJ, Herbst, RS, Minna, JD, Heymach, JV & Wistuba, II 2011, 'Increased VEGFR-2 gene copy is associated with chemoresistance and shorter survival in patients with non-small-cell lung carcinoma who receive adjuvant chemotherapy', Cancer Research, vol. 71, no. 16, pp. 5512-5521. https://doi.org/10.1158/0008-5472.CAN-10-2614
Yang, Fei ; Tang, Ximing ; Riquelme, Erick ; Behrens, Carmen ; Nilsson, Monique B. ; Giri, Uma ; Varella-Garcia, Marileila ; Byers, Lauren A. ; Lin, Heather Y. ; Wang, Jing ; Raso, Maria G. ; Girard, Luc ; Coombes, Kevin ; Lee, J. Jack ; Herbst, Roy S. ; Minna, John D. ; Heymach, John V. ; Wistuba, Ignacio I. / Increased VEGFR-2 gene copy is associated with chemoresistance and shorter survival in patients with non-small-cell lung carcinoma who receive adjuvant chemotherapy. In: Cancer Research. 2011 ; Vol. 71, No. 16. pp. 5512-5521.
@article{7bcfb1b376c44e8b92c83596bb6bf4d2,
title = "Increased VEGFR-2 gene copy is associated with chemoresistance and shorter survival in patients with non-small-cell lung carcinoma who receive adjuvant chemotherapy",
abstract = "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-1a 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.",
author = "Fei Yang and Ximing Tang and Erick Riquelme and Carmen Behrens and Nilsson, {Monique B.} and Uma Giri and Marileila Varella-Garcia and Byers, {Lauren A.} and Lin, {Heather Y.} and Jing Wang and Raso, {Maria G.} and Luc Girard and Kevin Coombes and Lee, {J. Jack} and Herbst, {Roy S.} and Minna, {John D.} and Heymach, {John V.} and Wistuba, {Ignacio I.}",
year = "2011",
month = "8",
day = "15",
doi = "10.1158/0008-5472.CAN-10-2614",
language = "English (US)",
volume = "71",
pages = "5512--5521",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "16",

}

TY - JOUR

T1 - Increased VEGFR-2 gene copy is associated with chemoresistance and shorter survival in patients with non-small-cell lung carcinoma who receive adjuvant chemotherapy

AU - Yang, Fei

AU - Tang, Ximing

AU - Riquelme, Erick

AU - Behrens, Carmen

AU - Nilsson, Monique B.

AU - Giri, Uma

AU - Varella-Garcia, Marileila

AU - Byers, Lauren A.

AU - Lin, Heather Y.

AU - Wang, Jing

AU - Raso, Maria G.

AU - Girard, Luc

AU - Coombes, Kevin

AU - Lee, J. Jack

AU - Herbst, Roy S.

AU - Minna, John D.

AU - Heymach, John V.

AU - Wistuba, Ignacio I.

PY - 2011/8/15

Y1 - 2011/8/15

N2 - 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-1a 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.

AB - 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-1a 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.

UR - http://www.scopus.com/inward/record.url?scp=80051676156&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80051676156&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-10-2614

DO - 10.1158/0008-5472.CAN-10-2614

M3 - Article

C2 - 21724587

AN - SCOPUS:80051676156

VL - 71

SP - 5512

EP - 5521

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 16

ER -