221 MET ECD shedding and use of targeted therapies and complete inhibition of tumor growth in vivo (55). Whether there is a molecular subtype of HNSCC, and more specifically OSCC, driven by MET mutation and/or amplification that confers a susceptibility to targeted agents, needs to be further examined in sufficiently large and well-described patient cohorts (7). In contrast, limited to no effects of MET-targeted therapies were observed on cell growth in wild-type MET tumor models (56). Nevertheless, pharmacological inhibition of wildtype MET has negative effects on cell survival from apoptotic insults, migration, and metastasis (57). This led to the notion that only patients whose primary tumors and/ or metastases are earmarked by MET-specific activating (oncogenic) mutations or amplification are likely to benefit from MET-targeted therapies (11). This also partially explains the contrasting literature reports on the success of MET-targeting agents. Yet, lack of genetic defects does not necessarily imply that MET-targeted therapies are ineffective in the wild-type setting. Several studies have shown that MET inhibitors can affect resistance to radio- and chemotherapy, and to cetuximab, a moAb directed against EGFR (53, 58). Moreover, activation of MET on dendritic cells in the TME can create a state of immunotolerance for cancer cells by down-regulating the inflammatory activity of T-cells through engaging their immune checkpoints (59, 60). More precisely, similar to cancer cells, dendritic cells can suppress an immune response by expressing surface molecules, such as programmed cell-death ligand 1 (PDL-1), that inhibit T-cells by binding to their membranous receptor programmed cell death protein 1 (PD-1). As such, inhibition of MET expressed by dendritic cells, might contribute to the re-initiation of the activity of T cells enabling them to kill cancer cells. Possibly the combined use of MET-targeted therapies and immune checkpoint inhibitors, i.e. PD-1, can restore an immune competent TME resulting in the killing of cancer cells (11). As CRT, cetuximab, and PD-1 inhibitors can be applied across different OSCC disease stages, MET remains an interesting target in the wild-type setting since its inhibition could further improve the performance of these treatment modalities (1, 11). Although MET immunoreactivity has been associated with advanced disease stage, tumor recurrence, and poor prognosis, no clear relationship has been established with response to MET-targeted therapy. Therefore, the use of MET immunoreactivity to facilitate the stratification of cancer patients into treatment categories is still a subject of debate (61). To begin with, it has been argued that MET immunoreactivity fails as a biomarker because it does not reflect MET activity. The possibility exists that MET is highly activated in low expressing tumors, e.g. if there are tumor areas with high levels of HGF in the TME (61). Additionally, oncogenic mutations triggering MET activation do not imply MET overexpression (62). As MET TKIs are 7
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