222 Chapter 7 designed to reduce MET phosphorylation, consequently reducing its signaling activity, it is argued that levels of phosphorylated MET (phospho-MET) immunoreactivity is a far better selection criterion for the inclusion of clinical trials than MET immunoreactivity (63). Unfortunately, use of unreliable phospho-MET antibodies led to conflicting results concerning the correlation between MET and phospho-MET immunoreactivity in non-small-cell lung cancers. Where Watermann et al. showed no correlation between MET and phospho-MET (64), Copin et al. showed phospho-MET in tumor areas that are strongly positive for MET (65). Thus far, no MET clinical trial has used phospho-MET as a selection criterion for participation, possibly leading to the inclusion of patients that will not benefit from treatment with the investigated agent. This is not only detrimental for the patients, but may also lead to the rejection of drugs with beneficial potential (61, 63). Another limitation in the use of MET immunoreactivity to predict response to treatment, is that scoring of MET immunoreactivity is generally restricted to the membrane. Since MET remains active post-endocytosis, facilitating downstream signaling, membranous scoring leads to an underestimation of MET activity. As such, new scoring methods need to be developed that take cytoplasmic MET immunoreactivity into account to further enhance patient selection and subsequent outcomes. Finally, all of the preclinical and clinical studies that have been reported to date make use of different antibodies, scoring systems, and inclusion criteria, thus limiting the validity and reproducibility of the observed outcomes (61). Conclusions As MET-EC- is associated with poor survival in C-terminal MET positive OSCC, it can lead to improved prediction of prognosis and a more contemplated choice on the use of type of targeted therapy (moAb and/or TKI). The fact that MET remains a target of interest in the wild-type setting (11), likely playing a role in therapy resistance, creates the need to develop guidelines concerning standardized use of MET and/or phospho-MET antibodies, scoring and evaluation in the form of companion diagnostics to improve the success of clinical trials investigating the effectiveness of MET-targeted therapies, in terms of better patient stratification and ultimately prolonged survival. It is suggested here that parallel use of C- and N-terminal MET antibodies should be incorporated in such guidelines, as it allows the identification of MET’s post-translational status, among which oncogenic MET-EC-, which transforming, invasive, and tumorigenic properties require further investigation in the field of OSCC.
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