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Anti‐tumor activity of the combination of cetuximab, an anti‐EGFR blocking monoclonal antibody and ZD6474, an inhibitor of VEGFR and EGFR tyrosine kinases
Author(s) -
Morelli Maria Pia,
Cascone Tina,
Troiani Teresa,
Tuccillo Concetta,
Bianco Roberto,
Normanno Nicola,
Romano Marco,
Veneziani Bianca Maria,
Fontanini Gabriella,
Eckhardt S. Gail,
De Pacido Sabino,
Tortora Giampaolo,
Ciardiello Fortunato
Publication year - 2006
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.20666
Subject(s) - cetuximab , autocrine signalling , epidermal growth factor receptor , cancer research , egfr inhibitors , tyrosine kinase , vascular endothelial growth factor , tyrosine kinase inhibitor , growth factor receptor , epidermal growth factor , pharmacology , medicine , colorectal cancer , receptor , cancer , vegf receptors
Purpose: The epidermal growth factor receptor (EGFR) autocrine pathway plays an important role in cancer cell growth. Vascular endothelial growth factor A (VEGF‐A) is a key regulator of tumor‐induced endothelial cell proliferation and vascular permeability. ZD6474 is an orally available, small molecule inhibitor of VEGF receptor‐2 (VEGFR‐2), EGFR and RET tyrosine kinase activity. We investigated the activity of ZD6474 in combination with cetuximab, an anti‐EGFR blocking monoclonal antibody, to determine the anti‐tumor activity of EGFR blockade through the combined use of two agents targeting the receptor at different molecular sites in cancer cells and of VEGFR‐2 blockade in endothelial cells. Experimental Design: The anti‐tumor activity in vitro and in vivo of ZD6474 and/or cetuximab was tested in human cancer cell lines with a functional EGFR autocrine pathway. Results: The combination of ZD6474 and cetuximab determined synergistic growth inhibition in all cancer cell lines tested as assessed by the Chou and Talalay method. In nude mice bearing established human colon carcinoma (GEO) or lung adenocarcinoma (A549) xenografts and treated with ZD6474 and/or cetuximab for 4 weeks, a reversible tumor growth inhibition was caused by each drug. In contrast, a more significant tumor growth delay resulted from the combination of the two agents with an approximately 100–110 days increase in mice median overall survival as compared to single agent treatment. Conclusions: This study provides a rationale for evaluating in a clinical setting the double blockade of EGFR in combination with inhibition of VEGFR‐2 signaling as cancer therapy. J. Cell. Physiol. 208: 344–353, 2006. © 2006 Wiley‐Liss, Inc.