Antiepidermal growth factor receptor therapy in squamous cell carcinoma of the head and neck

Abstract

Squamous cell carcinoma of head and neck (SCCHN) is the most common neoplasm of the upper aerodigestive tract. In this paper, we attempt to summarize the role and applications of the epidermal growth factor receptor (EGFR) inhibitors monoclonal antibodies (moAbs) and tyrosine kinase inhibitors (TKIs) locally advanced as well as metastatic SCCHN. Targeted therapy in SCCHN is now incorporated in the first-line regimes for advanced disease. Novel targeted agents, including the EGFR antibody, cetuximab, have been approved for use as single agents or in combination with radiation therapy or chemotherapy in treatment of recurrent metastatic or locally advanced SCCHN. Refractory mechanisms that bypass the pathway of EGFR inhibitors activity are identified explaining resistance to targeted therapy. Strategies of cotargeting EGFR and other pathways are under investigation. Examples of targeted therapy being used include mammalian target of rapamycin (mtor) inhibitors, antivascular endothelial growth factor (VEGF) moAb, and other inhibitors. We will be focusing our paper on the preclinical and clinical aspects of EGFR inhibition in SCCHN and touch upon other targeted therapies in application.

Figure 1

Schema of the EGFR activation pathway. EGFR is the transmembrane protein (green) with intrinsic tyrosine kinase (phosphorylation in yellow) activity that regulates cell growth. Its ligands are EGF, tumor necrosis factor alfa (TNFα) and others (red). Ligand binds to the receptor and initiates the activity of signaling pathways through dimerization of the receptor and autophosphorization of the tyrosine residues in the cytoplasm, which activates other downstream pathways including Janus Kinase (JAK) Signal Transducers and Activators of Transcription (STAT) directly and through phosphatidylinositol 4,5 bisphosphate (PIP2), c-Jun N-Terminal Kinase (JNK) and raf-1. Activation of these pathways leads to activation of STAT, c-Fos, c-Jun, and c-myc transcription factors respectively. These transcription factors regulate gene expression leading to cell cycle progression, proliferation, invasion, angiogenesis and metastasis.