The Occurrence of MET Ectodomain Shedding in Oral Cancer and Its Potential Impact on the Use of Targeted Therapies

The receptor tyrosine kinase MET has gained attention as a therapeutic target. Although MET immunoreactivity is associated with progressive disease, use of targeted therapies has not yet led to major survival benefits. A possible explanation is the lack of companion diagnostics (CDx) that account for proteolytic processing. During presenilin-regulated intramembrane proteolysis, MET's ectodomain is shed into the extracellular space, which is followed by γ-secretase-mediated cleavage of the residual membranous C-terminal fragment. The resulting intracellular fragment is degraded by the proteasome, leading to downregulation of MET signaling. Conversely, a membrane-bound MET fragment lacking the ectodomain (MET-EC^-) can confer malignant potential. Use of C- and N-terminal MET monoclonal antibodies (moAbs) has illustrated that MET-EC^- occurs in transmembranous C-terminal MET-positive oral squamous cell carcinoma (OSCC). Here, we propose that ectodomain shedding, resulting from G-protein-coupled receptor transactivation of epidermal growth factor receptor signaling, and/or overexpression of ADAM10/17 and/or MET, stabilizes and possibly activates MET-EC^- in OSCC. As MET-EC^- is associated with poor prognosis in OSCC, it potentially has impact on the use of targeted therapies. Therefore, MET-EC^- should be incorporated in the design of CDx to improve patient stratification and ultimately prolong survival. Hence, MET-EC^- requires further investigation seen its oncogenic and predictive properties.