Vascular endothelial growth factor receptor-1 contributes to resistance to anti-epidermal growth factor receptor drugs in human cancer cells.

Journal article

PURPOSE: The resistance to selective EGFR inhibitors involves the activation of alternative signaling pathways, and Akt activation and VEGF induction have been described in EGFR inhibitor-resistant tumors. Combined inhibition of EGFR and other signaling proteins has become a successful therapeutic approach, stimulating the search for further determinants of resistance as basis for novel therapeutic strategies. EXPERIMENTAL DESIGN: We established human cancer cell lines with various degrees of EGFR expression and sensitivity to EGFR inhibitors and analyzed signal transducers under the control of EGFR-dependent and EGFR-independent pathways. RESULTS: Multitargeted inhibitor vandetanib (ZD6474) inhibited the growth and the phosphorylation of Akt and its effector p70S6 kinase in both wild-type and EGFR inhibitor-resistant human colon, prostate, and breast cancer cells. We found that the resistant cell lines exhibit, as common feature, VEGFR-1/Flt-1 overexpression, increased secretion of VEGF and placental growth factor, and augmented migration capabilities and that vandetanib is able to antagonize them. Accordingly, a new kinase assay revealed that in addition to VEGF receptor (VEGFR)-2, RET, and EGFR, vandetanib efficiently inhibits also VEGFR-1. The contribution of VEGFR-1 to the resistant phenotype was further supported by the demonstration that VEGFR-1 silencing in resistant cells restored sensitivity to anti-EGFR drugs and impaired migration capabilities, whereas exogenous VEGFR-1 overexpression in wild-type cells conferred resistance to these agents. CONCLUSIONS: This study shows that VEGFR-1 contributes to anti-EGFR drug resistance in different human cancer cells. Moreover, vandetanib inhibits VEGFR-1 activation, cell proliferation, and migration, suggesting its potential utility in patients resistant to EGFR inhibitors.

Authors: Bianco, R; Rosa, R; Damiano, V; Daniele, G; Gelardi, T

• Publication status: Published
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research
• Volume: 14
• Issue: 16
• Pages: 5069-5080
• Publication date: 2008-08-01
• DOI: 10.1158/1078-0432.ccr-07-4905
• EISSN: 1557-3265
• ISSN: 1078-0432
• Language: English
• Keywords: Blotting, Western; Receptor, Epidermal Growth Factor; Humans; Piperidines; Antineoplastic Agents; Cell Movement; Cell Adhesion; Cell Proliferation; Quinazolines; Immunoprecipitation; RNA Interference; Drug Resistance, Neoplasm; Transfection; Neoplasms; Vascular Endothelial Growth Factor Receptor-1; Cell Line, Tumor; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction