85 MET ECD shedding and poor DFS Introduction Around 90% of all head and neck cancers are squamous cell carcinoma (1) and almost one third originates in the oral cavity (2). In general, the management of oral squamous cell carcinoma includes single modality surgery, radiotherapy, or combination of these modalities with or without systemic adjuvant therapy (chemotherapy and or targeted therapies) (2-5). Radiotherapy with or without chemotherapy is given; as an adjuvant to primary surgery to improve locoregional control in cases with unfavorable histopathological features, as primary treatment for cases unsuitable for surgery or as part of organ preservation schemes, and as a salvage treatment in cases with persistent or recurrent disease (2-5). Although increasingly aggressive chemotherapy and chemoradiotherapy result in high response rates and improved survival, the possibility exists that the point has been reached that further advances are outweighed by increased toxicities (6). This explains the interest for the use of targeted therapies in the treatment of these tumors (6). One target of interest is MET (6, 7), a transmembrane receptor tyrosine kinase (8) known to orchestrate invasive growth in head and neck squamous cell carcinoma (9). Although high MET expression is associated with poor prognosis in various solid cancers (8)—including head and neck squamous cell carcinoma (10)—and numerous targeted therapies are under investigation (11, 12), major survival benefits have not yet been established (12, 13). This, together with costs of approximately $100,000 per year of treatment per patient hampers the use of MET inhibitors in clinical practice (14, 15). One explanation for the lack of evidence of clinical benefit of MET inhibitors may be found in the absence of suitable companion diagnostics (13), defined as “a medical device, often an in vitro device, which provides information that is essential for the safe and effective use of a corresponding drug or biological product” (16). The development of companion diagnostics for targeted therapies directed against MET has been proven difficult for several reasons (13). Some are of technical nature, such as the lack of reliable antibodies and optimal scoring methods (10, 11, 13), while other reasons may be due to biology, such as ectodomain shedding (13). Similar to other receptors having intrinsic kinase activity, MET is subjective to proteolysis either dependent or independent of ligand stimulation (17). While performing the validation of a series of C-terminal MET antibodies using a panel of cell lines (18), we observed specific degradation patterns under reducing conditions. On the one hand, these patterns were explained by caspase cleavage of MET under con4
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