113 MET ECD shedding and poor DFS that induce ectodomain shedding having regulated intramembrane proteolysis as a consequence (39, 40). The latter strategy assumes that these monoclonal antibodies induce physiological ectodomain shedding and possibly prevents the occurrence of the oncogenic C-terminal fragment. Fig. 10: Proposed companion diagnostic for the use of targeted therapies directed against MET in oral squamous cell carcinoma. a MET negative cancers not eligible for treatment with targeted therapies directed against MET. b Cancers positive for the decoy receptors not eligible for treatment with targeted therapies directed against MET. c Cancers abundantly positive for the entire—both C- and N-terminal—MET receptor eligible for treatment with monoclonal antibodies and tyrosine kinase inhibitors. d Cancers subjective to shedding—≥35% of cancer cells—eligible for treatment with tyrosine kinase inhibitors, treatment strategies directed against proteins that orchestrate ectodomain shedding (e.g., ADAMs), monoclonal antibodies that induce ectodomain shedding having regulated intramembrane proteolysis as a consequence. To our knowledge we are the first to apply a combination of reliable C- and N-terminal MET antibodies to evaluate MET status in oral squamous cell carcinoma using immunohistochemistry. Taking this approach, we have not only shown the occurrence of MET ectodomain shedding in oral squamous cell carcinoma, but have also established its independent association with poor disease-free survival. Adding MET protein status to the diagnostic setting of patients diagnosed with oral squamous cell carcinoma, would add up to approximately $180 per patient (41). This seems 4
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