Treatment Therapies
Targeted therapies
Rationale for HER1/EGFR
The HER family comprises four structurally related transmembrane TK proteins including HER1/EGFR (also known as HER1 or ErbB1), HER2 (Erb2 or neu), HER3 (Erb3), and HER4 (Erb4). HER1/EGFR is found on almost all cells and binds to a specific set of endogenous ligands including epidermal growth factor (EGF) and transforming growth factor alpha (TGF-α). The binding of ligands to the extracellular domain promotes dimerisation of the receptors and autophosphorylation of their intracellular tyrosine residues. Once phosphorylated, the tyrosines are able to bind to SH2 domains of proteins that activate a number of intracellular signalling pathways, second messenger molecules and cascades, including RAS, GTPase-activating protein, RAF/mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase, and protein kinase C (Figure 1).1,2 Activation of HER1/EGFR in normal tissues contributes to cell proliferation, differentiation, migration, adhesion, protection from apoptosis and angiogenesis.3
Figure 1. Effects of HER1/EGFR activation.
HER1/EGFR plays a pivotal role in the growth and progression of human cancer. Dysregulation may occur as the result of receptor or ligand overproduction, mutations that lead to constitutive activation, decreased phosphatase activity or alterations in the downstream pathways. Given the normal function of HER1/EGFR, the biological consequence of its dysregulated activity is malignant transformation with the generation of aggressive tumour phenotypes that are insensitive to chemotherapy and radiation therapy.4,5 However, there is conflicting evidence as to the absolute prognostic value of HER1/EGFR expression, especially in late-stage NSCLC.1,6,7
With the increased understanding of the role that HER1/EGFR plays in tumourigenesis has come the development of new compounds and biological agents to specifically target aspects of its activity, e.g. monoclonal antibodies, small molecule TKIs, ligandtoxin conjugates and vaccines against EGF.8 The monoclonal antibody cetuximab competes with endogenous ligand binding to prevent HER1/EGFR dimerisation and subsequent cross-phosphorylation of the intracellular TK domains. This inhibits activities in tumour cells such as proliferation, angiogenesis, invasion and migration whilst promoting apoptosis.9 The small-molecule TKIs, such as gefitinib and Tarceva (erlotinib) compete with adenosine triphosphate for binding to the intracellular TK domain thereby inhibiting the kinase activity of HER1/EGFR in the presence of its ligand. The intracellular site of action also means that small-molecule TKIs like Tarceva are effective against EGFRvIII, a constitutively activated mutant form of HER1/EGFR that lacks the extracellular ligand-binding domain.
HER1/EGFR is expressed at very low levels in normal lung tissue where it is limited to the basal layer of the bronchial epithelium. However, expression increases progressively from metaplastic, through preneoplastic to neoplastic lesions and therefore represents an early marker of transformation.7 There is wide interpatient variation, but between 40% and 80% of resected NSCLC tumours overexpress HER1/EGFR10,11 or the constitutively activated EGFRvIII mutant.7
References:
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4. Brabender J, Daneneberg KD, Metzger R, et al. Epidermal growth factor receptor and HER2-neu mRNA expression in non-small cell lung cancer is correlated with survival. Clin Cancer Res 2001;7:1850–5.
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7. Meert A-P, Martin B, Delmotte P, et al. The role of EGF-R expression on patient survival in lung cancer: a systematic review with meta-analyses. Eur Respir J 2002;20:975–81.
8. Sridhar SS, Seymour L, Shepherd FA. Inhibitors of epidermal-growth factor receptors: a review of clinical research with a focus on non-small-cell lung cancer. Lancet Oncol 2003;4:397–406.
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10. Rusch V, Klimasata D, Venkatraman E, Pisters PW, Langenfeld J, Dmitrovsky E. Overexpression of epidermal growth factor receptor and its ligand transforming growth factor alpha is frequent in resectable non-small cell lung cancer but does not predict tumour progression. Clin Cancer Res 1997;3:515–22.
11. Fontanini G, De Laurentis M, Vignati S, et al. Evaluation of epidermal growth factorrelated 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;4:241–9.
