Elsevier

Pharmacological Research

Volume 79, January 2014, Pages 34-74
Pharmacological Research

Invited Review
The ErbB/HER family of protein-tyrosine kinases and cancer

This paper is dedicated to the memory of Dr. John W. Haycock (1949–2012) who prompted the author to write a review on the treatment of malignant diseases with targeted protein kinase inhibitors.
https://doi.org/10.1016/j.phrs.2013.11.002Get rights and content

Abstract

The human epidermal growth factor receptor (EGFR) family consists of four members that belong to the ErbB lineage of proteins (ErbB1–4). These receptors consist of a glycosylated extracellular domain, a single hydrophobic transmembrane segment, and an intracellular portion with a juxtamembrane segment, a protein kinase domain, and a carboxyterminal tail. Seven ligands bind to EGFR including epidermal growth factor and transforming growth factor α, none bind to ErbB2, two bind to ErbB3, and seven ligands bind to ErbB4. The ErbB proteins function as homo and heterodimers. The heterodimer consisting of ErbB2, which lacks a ligand, and ErbB3, which is kinase impaired, is surprisingly the most robust signaling complex of the ErbB family. Growth factor binding to EGFR induces a large conformational change in the extracellular domain, which leads to the exposure of a dimerization arm in domain II of the extracellular segment. Two ligand-EGFR complexes unite to form a back-to-back dimer in which the ligands are on opposite sides of the aggregate. Following ligand binding, EGFR intracellular kinase domains form an asymmetric homodimer that resembles the heterodimer formed by cyclin and cyclin-dependent kinase. The carboxyterminal lobe of the activator kinase of the dimer interacts with the amino-terminal lobe of the receiver kinase thereby leading to its allosteric stimulation. Downstream ErbB signaling modules include the phosphatidylinositol 3-kinase/Akt (PKB) pathway, the Ras/Raf/MEK/ERK1/2 pathway, and the phospholipase C (PLCγ) pathway. Several malignancies are associated with the mutation or increased expression of members of the ErbB family including lung, breast, stomach, colorectal, head and neck, and pancreatic carcinomas and glioblastoma (a brain tumor). Gefitinib, erlotinib, and afatinib are orally effective protein-kinase targeted quinazoline derivatives that are used in the treatment of ERBB1-mutant lung cancer. Lapatinib is an orally effective quinazoline derivative used in the treatment of ErbB2-overexpressing breast cancer. Trastuzumab, pertuzumab, and ado-trastuzumab emtansine, which are given intravenously, are monoclonal antibodies that target the extracellular domain and are used for the treatment of ErbB2-positive breast cancer; ado-trastuzumab emtansine is an antibody-drug conjugate that delivers a cytotoxic drug to cells overexpressing ErbB2. Cetuximab and panitumumab are monoclonal antibodies that target ErbB1 and are used in the treatment of colorectal cancer. Cancers treated with these targeted drugs eventually become resistant to them. The role of combinations of targeted drugs or targeted drugs with cytotoxic therapies is being explored in an effort to prevent or delay drug resistance in the treatment of these malignancies.

Introduction

The ErbB/HER protein-tyrosine kinases, which include the epidermal growth factor receptor, are among the most studied cell signaling families in biology [1]. Cohen initiated this line of investigation and described epidermal growth factor (EGF), its receptor (EGFR), and its biochemical actions [2]. He discovered that the EGF receptor was a protein-tyrosine kinase, which was a revolutionary finding at the time (see Ref. [3] for a historical review). Cohen et al. found that a solubilized 170 kDa polypeptide contains both EGF binding activity and protein kinase activity [4]. EGFR was also the first receptor that provided evidence for a relationship between receptor overexpression and cancer [5]. EGFR is among the most studied receptor protein-tyrosine kinases owing to its general role in signal transduction and in oncogenesis.

The human protein kinase family consists of more than 500 members thereby making it one of the largest gene families [6]. These enzymes catalyze the following reaction:MgATP−1 + proteinsingle bondOH  Proteinsingle bondOPO32− + MgADP + H+

Based upon the nature of the phosphorylated single bondOH group, these proteins are classified as protein-serine/threonine kinases (385 members), protein-tyrosine kinases (90 members), and tyrosine-kinase like proteins (43 members). Moreover, there are 106 protein kinase pseudogenes. Of the 90 protein-tyrosine kinases, 58 are receptor and 32 are non-receptor kinases. A small group of dual-specificity kinases including MEK1 and MEK2 catalyze the phosphorylation of both tyrosine and threonine in target proteins; dual-specificity kinases possess molecular features that place them within the protein-serine/threonine kinase family. Protein phosphorylation is the most widespread class of post-translational modification used in signal transduction. Families of protein phosphatases catalyze the dephosphorylation of proteins thus making phosphorylation–dephosphorylation an overall reversible process [7].

Protein kinases play a predominant regulatory role in nearly every aspect of cell biology [6]. They regulate apoptosis, cell cycle progression, cytoskeletal rearrangement, differentiation, development, the immune response, nervous system function, and transcription. Moreover, dysregulation of protein kinases occurs in a variety of diseases including cancer, diabetes, and autoimmune, cardiovascular, inflammatory, and nervous disorders. Considerable effort has been expended to determine the physiological and pathological functions of receptor protein-kinase signal transduction pathways during the past 30 years.

Section snippets

ErbB protein kinases

The human EGF receptor family consists of four members (HER1–4) that belong to the ErbB lineage of proteins (ErbB1–4). This family of receptors is ubiquitously expressed in epithelial, mesenchymal, and neuronal cells and their cellular progenitors. The gene symbol, ERBB, is derived from the name of the avian viral erythroblastosis oncogene to which these receptors are related. Human gene symbols generally are italicized with all letters in uppercase (EGFR). Italics are not necessary in gene

The extracellular ligand-binding domains

Binding of growth factors to ErbB1/3/4 promotes dimerization of monomeric receptors and increases the tyrosyl kinase activity of the intracellular domains of ErbB1/2/4 [32]. Although ErbB2 lacks a soluble ligand or growth factor, it readily forms heterodimers. There are a number of possible ways that a growth factor or ligand can induce receptor dimerization. One possibility for growth-factor induced receptor dimerization involves a single ligand that interacts simultaneously with two receptor

ErbB signaling

The ErbB/HER signaling networks consist of several modules that are interconnected and overlapping [80]. These include the phosphatidylinositol 3-kinase (PI3K)/Akt (PKB) pathway, the Ras/Raf/MEK/ERK1/2 pathway, and the phospholipase C (PLCγ) pathway. The PI3K/Akt pathway plays an important role in mediating cell survival and the Ras/ERK1/2 and PLCγ pathways participate in cell proliferation [81]. These and other ErbB signaling modules participate in angiogenesis, cell adhesion, cell motility,

Classification and general treatment

Lung cancer is the most prevalent malignancy in the world [140]. In 2008, the estimated global incidence of lung cancer was about 1.6 million with about 1.4 million deaths attributed to this malignancy. In 2012, the estimated incidence of lung cancer in the United States was about 228,000 with about 160,000 deaths [141]. These data indicate that lung cancer is a disease of high mortality and that more effective treatments are needed. Lung cancers are classified clinically into two major groups:

Orally active ErbB protein kinase domain inhibitors, Lipinski's rule of five, lipophilic efficiency, and ligand efficiency

Pharmacologists and medicinal chemists have searched for drug-like chemical properties that result in compounds with oral therapeutic efficacy in a predictable fashion. Lipinski's “rule of five” represents an initial experimental and computational approach to estimate solubility, permeability, and efficacy in the drug discovery and development setting [270]. This rule predicts that poor absorption or permeation is more likely when there are more than 5 hydrogen-bond donors, 10 (5 × 2)

Adverse effects and toxicity of non-targeted and targeted anticancer agents

Although nearly all drugs have associated adverse side-effects and toxicities, these are considerably more serious for cytotoxic drugs than for targeted agents [146]. Cytotoxic agents indiscriminately cause macromolecular lesions whereas targeted therapies regulate the activity of specific signaling pathways. The cytotoxic agents are poisons that wreak havoc on the recipient; moreover, many of them are administered at the maximum tolerated dose. The term pharmaceutical is derived from pharmacon

Conflict of interest

The author is unaware of any affiliations, memberships, or financial holdings that might be perceived as affecting the objectivity of this review.

Acknowledgements

The author thanks Prof. John Kuriyan for providing the protein data bank file for the EGFR asymmetric dimer. He also thanks the library staff of the University of North Carolina at Chapel Hill Health Sciences library for providing bibliographic assistance and Laura M. Roskoski for providing editorial support.

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