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  • Review Article
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Combined targeting of EGFR-dependent and VEGF-dependent pathways: rationale, preclinical studies and clinical applications

Nature Clinical Practice Oncology volume 5, pages 521–530 (2008)Cite this article

Abstract

Cellular heterogeneity, redundancy of molecular pathways and effects of the microenvironment contribute to the survival, motility and metastasis of cells in solid tumors. It is unlikely that tumors are entirely dependent on only one abnormally activated signaling pathway; consequently, treatment with an agent that interferes with a single target may be insufficient. Combined blockade of functionally linked and relevant multiple targets has become an attractive therapeutic strategy. The EGFR and ERBB2 (HER2) pathways and VEGF-dependent angiogenesis have a pivotal role in cancer pathogenesis and progression. Robust experimental evidence has shown that these pathways are functionally linked and has demonstrated a suggested role for VEGF in the acquired resistance to anti-ERBB drugs when these receptors are pharmacologically blocked. Combined inhibition of ERBB and VEGF signaling interferes with a molecular feedback loop responsible for acquired resistance to anti-ERBB agents and promotes apoptosis while ablating tumor-induced angiogenesis. To this aim, either two agents highly selective against VEGF and ERBB respectively, or, alternatively, a single multitargeted agent, can be used. Preclinical studies have proven the efficacy of both these approaches and early clinical studies have provided encouraging results. This Review discusses the experimental rationale for, preclinical studies of and clinical trials on combined blockade of ERBB and VEGF signaling.

Key Points

  • The heterogeneity of tumors and the wide degree of crosstalk among different signaling pathways compel a therapeutic approach directed against multiple complementary targets

  • EGFR, ERBB2 and VEGF have close functional interactions, control tumor and endothelial cell compartments, and are involved directly in the mechanisms of resistance to current therapies

  • Combined targeting of ERBB receptors and VEGF-dependent signaling has proven to be a successful strategy in preclinical studies and has been translated to the clinical setting

  • There are two main strategies pursued in preclinical and clinical studies—the first is based on the combination of two selective agents, including monoclonal antibodies and small-molecule tyrosine kinase inhibitors that target ERBB and VEGF, and the second on single multitargeted small-molecule inhibitors that simultaneously block VEGF receptors and ERBB

  • Both approaches have been used in early clinical studies in different types of cancer, and activity has been obtained in different tumors, especially in non-small-cell lung cancer

  • The safety profile of multitargeted agents is generally good, and adverse effects seem to occur by the addition of chemotherapeutic regimens

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Authors and Affiliations

  1. G Tortora is Associate Professor of Medical Oncology and Director of the Clinical Unit and Laboratories of Molecular Therapy at the University of Naples Federico II, Naples, F Ciardiello is Associate Professor of Medical Oncology and Head of the Laboratories of Cancer Therapy at the Second University of Naples,

    Giampaolo Tortora & Fortunato Ciardiello

  2. G Gasparini is Director and Head of the Division of Medical Oncology at the San Filippo Neri Hospital, Rome, Italy.,

    Giampietro Gasparini

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  1. Giampaolo Tortora
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  2. Fortunato Ciardiello
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  3. Giampietro Gasparini
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Correspondence to Giampaolo Tortora.

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Tortora, G., Ciardiello, F. & Gasparini, G. Combined targeting of EGFR-dependent and VEGF-dependent pathways: rationale, preclinical studies and clinical applications. Nat Rev Clin Oncol 5, 521–530 (2008). https://doi.org/10.1038/ncponc1161

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