Targeting EGF-receptor-signalling in squamous cell carcinomas of the head and neck

Abstract

Despite significant advances in the use of surgery, chemotherapy and radiotherapy to treat squamous cell carcinoma of the head and neck (SCCHN), prognosis has improved little over the past 30 years. There is a clear need for novel, more effective therapies to prevent relapse, control metastases and improve overall survival. Improved understanding of SCCHN disease biology has led to the introduction of molecularly targeted treatment strategies in these cancers. The epidermal growth factor receptor (EGFR) is expressed at much higher levels in SCCHN tumours than in normal epithelial tissue, and EGFR expression correlates with poor prognosis. Therefore, much effort is currently directed toward targeting aberrant EGFR activity (e.g. cell signalling) in SCCHN. This review discusses the efficacy of novel therapies targeting the EGFR (e.g. anti-EGFR antibodies and EGFR tyrosine kinase inhibitors) that are currently tested in SCCHN patients.

Figure 1

Intracellular signalling of the EGFR. Shown are the major signalling pathways downstream of c-erbB-receptors (e.g. EGFR). Modified after Rogers et al (2005) and Kalyankrishna and Grandis (2006). Binding of specific ligands (e.g. EGF, heparin-binding EGF, TGF-α, amphiregulin, betacellulin and heregulin) may generate up to 10 types of homo- or heterodimeric complexes resulting in conformational changes in the intracellular EGFR kinase domain, which lead to autophosphorylation and activation. Consequently, signalling molecules, including growth factor receptor-bound protein-2 (Grb-2), Shc and IRS-1 are recruited to the plasma membrane. G-protein coupled receptors can also activate EGFR in a ligand-independent manner by Src-mediated direct phosphorylation of Y-845. Insulin-like growth factor-1 receptor can also transactivate the EGFR. Activation of several signalling cascades is triggered predominately by the RAS-to-MAPK and the PI-3K/Akt pathways, resulting in enhanced tumour growth, survival, invasion and metastasis.

Figure 2

Preclinical and clinical development of Mabs and TKIs targeting the EGFR in SCCHN. The Mabs (light grey arrows), tested to date, include IMC-C225 (cetuximab), ICR62, ABX-EGF (panitumumab), EMD72000 (matuzumab), h-R3 (nimotuzumab), 2F8 (zalutumumab) and ch806. Cetuximab (IMC-C225) has been approved for use in SCCHN by both the FDA and EMEA in combination with radiotherapy. Nimotuzumab (h-R3) was recently approved for head and neck cancer in Argentina, Cuba, Columbia, China and India. ch806 is an EGFRvIII-specific Mab. Tyrosine kinase inhibitors (dark grey arrows) in clinical development include the EGFR inhibitors ZD1839 (gefitinib) and OSI-774 (erlotinib; formerly known as CP-358-774) as well as the EGFR/HER-2 inhibitor GW572016 (lapatinib).