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

Abstract

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: Roberto Bianco, Roberta Rosa, Vincenzo Damiano, Gennaro Daniele, Teresa Gelardi, Sonia Garofalo, Valeria Tarallo, Sandro De Falco, Davide Melisi, Roberto Benelli, Adriana Albini, Anderson Ryan, Fortunato Ciardiello, Giampaolo Tortora
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 16 Pg. 5069-80 (Aug 15 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18694994 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Piperidines
• Quinazolines
• ErbB Receptors
• Vascular Endothelial Growth Factor Receptor-1
• vandetanib

Topics

• Antineoplastic Agents (pharmacology)
• Blotting, Western
• Cell Adhesion (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (physiology)
• ErbB Receptors (antagonists & inhibitors, drug effects)
• Humans
• Immunoprecipitation
• Neoplasms (drug therapy, metabolism)
• Piperidines (pharmacology)
• Quinazolines (pharmacology)
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (physiology)
• Transfection
• Vascular Endothelial Growth Factor Receptor-1 (drug effects, metabolism)