214 Chapter 7 In up to 25% of HNSCC, MET is aberrantly activated by mutations and amplifications (7). Specifically, somatic mutations affecting the kinase domain are observed at a rate of around 8%, among which Y1230C, Y1235D (7). The Y1230C and Y1235D mutations constitutively activate MET and both mutations were found in lymph node metastasis of HNSCC (17). Interestingly, transcripts of the Y1235D mutant alleles are highly represented in regional lymph node metastasis, and barely detectable in the corresponding primary tumors, suggesting that cells carrying mutant MET undergo clonal expansion during HNSCC disease progression (17). Despite a variety of scoring methods and definitions, MET gene amplifications have been reported to occur in 1-13% of HNSCC (7). Although reported, the biological and clinical consequences of MET amplification in HNSCC need to be further investigated (7). In the majority of cancers, including HNSCC, MET is transcriptionally activated by stimuli such as hypoxia, inflammatory cytokines, stromal HGF, and pro-angiogenic factors, often abundantly present in the reactive tumor-associated stroma (7, 13, 18, 19). In this context, MET activation occurs in already transformed cells to increase their proliferative, anti-apoptotic, and migratory potential (13). Although MET expression is known to be associated with poor prognosis in HNSCC (20) and numerous targeted therapies are under investigation (12, 21), major survival benefits have not yet been obtained (21, 22). This could be due to a lack of relevant companion diagnostics (22, 23), of which development has been proven difficult for several reasons (22). Some are of a technical nature, such as lack of reliable antibodies (Abs) and scoring systems (12, 20, 22), while other may be due to biology, such as proteolytic processing and more specifically ectodomain shedding (22, 24). MET’s protein structure and its degradation The structural characterization of MET was initially resolved using COOH-terminal (C-terminal) MET antibodies (25) directed against the intracellular part of the receptor. It was discovered that the MET proto-oncogene (26-28) encodes a partially glycosylated 170 kDa single-chain intracellular precursor (p170MET) that undergoes terminal glycosylation and proteolytic cleavage yielding mature MET (p190MET) (29). The latter is a cell-surface-associated heterodimer composed of two disulfide-linked chains. More specifically, an extracellular 50 kDa α-chain (p50α) and a 145 kDa transmembranous β-chain (p145β) possessing the intracellular tyrosine kinase domain (27, 29-31).
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