ErbB receptor tyrosine kinase inhibitors as therapeutic agents

Front Biosci. 2002 Sep 1:7:d1926-40. doi: 10.2741/A889.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acid Sequence
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Drug Resistance, Neoplasm
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / chemistry
  • ErbB Receptors / physiology
  • Humans
  • Molecular Sequence Data
  • Neoplasms / drug therapy*
  • Neoplasms / etiology
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / chemistry
  • Receptor, ErbB-2 / physiology
  • Receptor, ErbB-3 / antagonists & inhibitors
  • Receptor, ErbB-3 / chemistry
  • Receptor, ErbB-3 / physiology
  • Receptor, ErbB-4
  • Sequence Homology, Amino Acid
  • Signal Transduction

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • ERBB4 protein, human
  • ErbB Receptors
  • Receptor Protein-Tyrosine Kinases
  • Receptor, ErbB-2
  • Receptor, ErbB-3
  • Receptor, ErbB-4