Overview of epidermal growth factor receptor biology and its role as a therapeutic target in human neoplasia,☆☆,

https://doi.org/10.1016/S0093-7754(02)70085-7Get rights and content

Abstract

The ability of the epidermal growth factor receptor (EGFR) to transform epithelial cells, the overexpression of EGFR and its ligands in several human carcinomas, and the causal association of the receptor network with accelerated tumor progression provided a rationale for targeting this signaling system with tumor-selective strategies. Two of these antireceptor approaches, both based on the known structure/function of the EGFR, will be discussed. The first strategy involved the development of humanized monoclonal antibodies against the nonconserved receptor's extracellular domain. These antibodies block ligand binding and can induce receptor downregulation. The second approach was the generation of adenosine triphosphate-mimetics that compete with adenosine triphosphate for binding to the receptor's kinase pocket and disable the ability of the EGFR to transduce intracellular signals. Early clinical studies already suggest that both of these approaches, either alone or in combination with standard anticancer therapies, alter the natural history of EGFR-expressing cancers with little toxicity to the tumor-bearing host. Semin Oncol 29 (suppl 14):3-9. Copyright 2002, Elsevier Science (USA). All rights reserved.

Section snippets

Signal transduction by the epidermal growth factor receptor network

THE EPIDERMAL growth factor receptor (EGFR) (also known as HER1 or erbB1) is a ubiquitous 170-kd membrane-spanning glycoprotein composed of an amino-terminal extracellular (EC) ligand-binding domain, a hydrophobic single transmembrane helix, a cytoplasmic domain containing the tyrosine kinase domain, and a carboxy-terminal region containing critical tyrosine residues and receptor regulatory motifs.1 Binding of a specific set of ligands (EGF, transforming growth factor-alpha [TGF-α],

Role of epidermal growth factor receptor signaling in transformation and tumor progression

Signaling by the EGFR and the erbB receptor network serves a crucial role in epithelial development, proliferation, and organogenesis. Oncogenic activation of this pathway occurs as a result of EGFR mutation, overexpression, structural rearrangements, and/or relief of its normal autoinhibitory and regulatory constraints. Mutations of the EGFR, like that encoded by v-erbB, are most common in nonhuman neoplasias.5 Transfection of high levels of EGFR and its ligand, TGF-α, has been shown to induce

Rationale in support of the epidermal growth factor receptor network as a therapeutic target

The coexpression of EGFR and ligands at tumor sites allows for EGFR activation via autocrine/paracrine mechanisms. In support of the operational nature of these signaling pathways in EGFR-expressing tumor cells, interruption of signaling with various EGFR inhibitors has been shown to inhibit tumor cell proliferation and/or viability both in vitro and in vivo.28, 29 These observations coupled with (1) the ability to identify EGFR-expressing human tumors in diagnostic tissue from patients, (2)

Molecular strategies to block epidermal growth factor receptor function: Receptor antibodies

One antireceptor strategy has been the use of monoclonal antibodies that recognize the receptor's ectodomain, compete for ligand binding, and induce EGFR dimerization and downregulation from the cell surface (Fig 2).

. Mechanisms of action of EGFR inhibitors. Antibodies prevent ligand access to the EGFR and induce receptor endocytosis. In some cases, this may result in targeting the receptor to a lysosomal compartment. Low-molecular-weight receptor tyrosine kinase inhibitors diffuse into the cell

Low-molecular-weight epidermal growth factor receptor tyrosine kinase inhibitors

A second antisignaling strategy was based on the observation that mutations in the adenosine triphosphate (ATP)-binding pocket of the EGFR (Fig 2) severely affect its tyrosine kinase function30 and the ability of the EGFR to transform cells. This strategy has involved the random screening of small molecules that compete for the Mg-ATP binding site of the catalytic domain of the EGFR tyrosine kinase from natural or synthetic compound libraries.45 Table 1 shows a list of the EGFR tyrosine kinase

Conclusions

It was less than 20 years ago when it was discovered that the EGFR is the cellular proto-oncogene of a mutant EGFR that induces avian erythroblastosis. The high levels of EGFR and its ligands in several common human carcinomas led to drug discovery and preclinical studies that supported the use of this signaling network as a target for novel treatment approaches. Many questions about the clinical development of these strategies remain unanswered. Of particular importance are the issue of tests

References (59)

  • AO Moniola et al.

    The erbB signaling network: Receptor heterodimerization in development and cancer

    EMBO J

    (2000)
  • J Downward et al.

    Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences

    Nature

    (1984)
  • EP Sandgreen et al.

    Overexpression of TGFα in transgenic mice: Induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast

    Cell

    (1990)
  • Y Kokai et al.

    Synergistic interaction of p185c-neu and the EGF receptor leads to transformation of rodent fibroblasts

    Cell

    (1987)
  • WJ Muller et al.

    Synergistic interaction of the Neu proto-oncogene product and transforming growth factor alpha in the mammary epithelium of transgenic mice

    Mol Cell Biol

    (1996)
  • V Rusch et al.

    Differential expression of the epidermal growth factor receptor and its ligands in primary non–small cell lung cancers and adjacent benign lung

    Cancer Res

    (1993)
  • JG Klijn et al.

    The clinical significance of epidermal growth factor receptor (EGF-R) in human breast cancer: a review on 5232 patients

    Endocr Rev

    (1992)
  • JR Grandis et al.

    Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival

    J Natl Cancer Inst

    (1998)
  • Y Yonemura et al.

    Interrelationship between transforming growth factor-alpha and epidermal growth factor receptor in advanced gastric cancer

    Oncology

    (1992)
  • T Hirai et al.

    Clinical results of transhiatal esophagectomy for carcinoma of the lower thoracic esophagus according to biological markers

    Dis Esophagus

    (1998)
  • M Tateishi et al.

    Immunohistochemical evidence of autocrine growth factors in adenocarcinoma of the human lung

    Cancer Res

    (1990)
  • Y Yamanaka et al.

    Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness

    Anticancer Res

    (1993)
  • AJ Ekstrand et al.

    Genes for epidermal growth factor receptor, transforming growth factor alpha, and epidermal growth factor and their expression in human gliomas in vivo

    Cancer Res

    (1991)
  • G Fontanini et al.

    Evaluation of epidermal growth factor-related growth factors and receptors and of neoangiogenesis in completely resected stage I-IIIA non–small-cell lung cancer: Amphiregulin and microvessel count are independent prognostic indicators of survival

    Clin Cancer Res

    (1998)
  • W Xia et al.

    Combination of EGFR, HER-2/neu, and HER-3 is a stronger predictor for the outcome of oral squamous cell carcinoma than any individual family members

    Clin Cancer Res

    (1999)
  • HI Scher et al.

    Changing pattern of expression of the epidermal growth factor receptor and transforming growth factor-alpha in the progression of prostatic neoplasms

    Clin Cancer Res

    (1995)
  • JG Klijn et al.

    The prognostic value of epidermal growth factor receptor (EGF-R) in primary breast cancer: Results of a 10 year follow-up study

    Breast Cancer Res Treat

    (1994)
  • D Veale et al.

    The relationship of quantitative epidermal growth factor receptor expression in non–small cell lung cancer to long term survival

    Br J Cancer

    (1993)
  • JM Bartlett et al.

    The prognostic value of epidermal growth factor receptor mRNA expression in primary ovarian cancer

    Br J Cancer

    (1996)
  • Cited by (281)

    • Non-small-cell lung cancer-associated gene mutations and inhibitors

      2022, Advances in Cancer Biology - Metastasis
    • Casein kinase 2 inhibitor CX-4945 elicits an anti-Warburg effects through the downregulation of TAp73 and inhibits gastric tumorigenesis

      2020, Biochemical and Biophysical Research Communications
      Citation Excerpt :

      Therefore, the main treatment for those patients with advanced gastric cancer is the non-surgical therapies including neoadjuvant chemoradiotherapy, molecular-targeted therapy, and immunotherapy [3]. In the past decades, significant advances have been achieved in molecular-targeted therapy [4–6]. However, most targeted drugs affect only a single target; therefore, the efficiency and efficacy of antitumor therapy is often unsatisfied.

    • Resistance to EGFR targeting treatments in colorectal cancer

      2019, Oncogenomics: From Basic Research to Precision Medicine
    • Targeted EGFR Nanotherapy in Non-Small Cell Lung Cancer

      2023, Journal of Functional Biomaterials
    View all citing articles on Scopus

    Supported in part by National Institutes of Health grant no. R01 CA80195, the Susan G. Komen Breast Cancer Foundation, and Vanderbilt-Ingram Cancer Center support grant no. CA68485.

    ☆☆

    Dr Arteaga has received research grant support from Genentech BioOncology. He has served as a consultant to and received honoraria from AstraZeneca and Genentech BioOncology.

    Address reprint requests to Carlos L. Arteaga, MD, Division of Hematology-Oncology, Vanderbilt University School of Medicine, 2220 Pierce Ave, 777 Preston Research Bldg, Nashville, TN 37232-6307.

    View full text