212 Chapter 7 Introduction: receptor tyrosine kinase MET, a suitable target for therapy in oral cancer? Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and comprises epithelial cancers of the upper aero/digestive tract originating in the oral cavity, oropharynx, hypopharynx, or larynx (1). Approximately 50% of HNSCC originate in the oral cavity (2). Depending on disease stage, the treatment of oral squamous cell carcinoma (OSCC) patients consists of single modality surgery, or in combination with radiotherapy with or without systemic adjuvant chemotherapy, commonly referred to as chemo-radiotherapy or chemo-radiation (CRT) (1). Notwithstanding the advances in these modalities, the 5-year survival rate of OSCC patients is still around 50% (1, 3, 4). As such, implementation of targeted therapies directed against signaling molecules known to facilitate HNSCC disease progression has gained much attention (5). One target of interest is the predominantly epithelial receptor tyrosine kinase (RTK) MET (5, 6), often upregulated in HNSCC (7). Upon binding to its extracellular ligand, hepatocyte growth factor/scatter factor (HGF/SF) (8, 9), which stimulates receptor dimerization and kinase activity (10), MET facilitates invasive growth by activating a complex network of signaling cascades, including MAPK, PI3K-Akt, STAT, and IκBαNFκB (11-13). During invasive growth, cancer cells integrate proliferation, survival, motility, and epithelial-to-mesenchymal transition (11), a program that converts epithelial cells into more mesenchymal derivatives that has emerged as a central driver of tumor malignancy (14) (Figure 1A).
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