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-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
• Journal: Cancer research (Cancer Res) Vol. 71 Issue 16 Pg. 5512-21 (Aug 15 2011) ISSN: 1538-7445 [Electronic] United States
• PMID: 21724587 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Vascular Endothelial Growth Factor Receptor-2

Topics

• 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)