[Frontiers in Bioscience 7, d1926-1940, September 1, 2002]

ErbB RECEPTOR TYROSINE KINASE INHIBITORS AS THERAPEUTIC AGENTS

Neil G Anderson & Tawhid Ahmad

Division of Cancer Studies, School of Medicine, University of Manchester, Oxford Road, Manchester M13 9PT

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Structure and biological functions of ErbB receptors
4. Regulation of receptor activity
4.1. ErbB Ligands
4.2. Receptor activation and signaling
4.3. Receptor transactivation
5. ErbB receptors and cancer
6. ErbB receptor tyrosine kinase inhibitors (TKIs)
6.1. History
6.2. Current status
6.3. Modes of action of inhibitors
6.4. Cancer cell processes affected by ErbB receptor TKIs
6.4.1. Proliferation
6.4.2. Apoptosis/survival
6.4.3. Invasion and metastasis
6.4.4. Angiogenesis
7. Considerations in the use of ErbB receptor TKIs as therapeutic agents
7.1. EGFR expression level does not predict responsiveness to EGFR TKIs
7.2. ErbB receptor TKIs in combination with other anticancer drugs
7.3. Comparisons with other ErbB receptor-targeted therapies
8. Perspective
9. Acknowledgments
10. References

1. ABSTRACT

The ErbB family of receptor tyrosine kinases comprise four members: EGFR, ErbB2, ErbB3 and ErbB4. All are essential for normal development and participate in the functioning of normal cells. ErbB receptors, particularly EGFR and ErbB2 are commonly deregulated in certain prevalent forms of human cancer. Recently a number of small molecule inhibitors of the tyrosine kinase activity of these receptors have been developed. Some of these agents, known as TKIs, are progressing through clinical trials in patients with aberrant ErbB receptor expression in their tumors. This article provides a brief overview on the structure and biology of ErbB receptors and their ligands before discussing in detail the development and current status of ErbB receptor TKIs. These agents are shown to inhibit multiple features of cancer cells including proliferation, survival, invasion and angiogenesis. It is clear from recent studies that not all cancer cells that overexpress ErbB receptors will be sensitive to TKIs. Potential explanations for resistance to these molecules are reviewed. Finally the prospect of using TKIs in combination with existing chemotherapeutic agents is discussed.