Targeting EGFR and VEGF(R) pathway cross-talk in tumor survival and angiogenesis

Abstract

The last decade has witnessed the approval of monoclonal antibodies (mAbs) and small molecule tyrosine kinase inhibitors (TKIs) for targeting of oncogenic signaling pathways. Generally, the clinical activity of these agents has been less than expected, in part due to unsuspected feed-back loops and cross-talk between different signaling pathways, thereby suggesting the interest of inhibiting multiple pathways. The extensive degree of EGFR-VEGF(R) pathway cross-talk identifies these pathways as particularly promising for joint targeting. Activation of the EGFR pathway increases the production of tumor-derived VEGF that acts on endothelial cells in a paracrine manner to promote angiogenesis. Accordingly, exposure to EGFR inhibitors is accompanied by attenuation of VEGF expression while resistance to EGFR inhibitors is frequently associated with enhanced VEGF levels. Recent data have expanded the biological activities of the two pathways by documenting a role for VEGF signaling in tumor cell survival and demonstrating the expression of EGFR by some tumor-associated endothelial cells. At least part of these signaling events are intracrine (intracellular and autocrine) and thus not readily accessible for the mAbs which target extracellular ligands and membrane receptors. This may explain why two major clinical trials combining EGFR and VEGF-targeted mAbs gave disappointing results and suggest a need for compounds that are able to inhibit intracrine signaling. Clinical application of new combinations should be preceded by preclinical development guided by functional biomarker analysis to identify active drug combinations and to facilitate the identification of patient subgroups likely, or not, to respond to dual pathway inhibition.

Introduction

The new millennium heralded the advent of targeted agents for cancer therapy including both monoclonal antibodies (mAbs) and small molecule tyrosine kinase inhibitors (TKIs). One decade later the outcome is mixed. Although targeted therapies clearly represent a conceptual break-through, the clinical activity has been less than expected, and it is becoming increasingly clear that most targeted therapies will only benefit patient subpopulations. The preclinical and clinical experiences have also underlined the importance of unsuspected feed-back loops and cross-talk between different signaling pathways. As a result, much effort is currently focused on attempts to target several signaling pathways at the same time (Gossage & Eisen, 2010).

This review will focus on the multiple interactions between the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) signaling pathways which make them attractive candidates for joint targeting. While the development of EGFR and VEGF(R)-targeted agents was only possible due to progress in cognitive tumor biology, the preclinical and clinical uses of these agents have identified many novel aspects of EGFR and VEGF signaling, illustrating the dynamic interplay between fundamental and applied cancer research.