239 General discussion, conclusion, and future perspective Furthermore, it was argued (chapter 3) that the association of absent membranous MET immunoreactivity with poor prognosis did not stand on its own, as a similar observation was observed for ERBB2 expression, another RTK involved in primary breast cancers (54). In retrospect, some nuances have to be applied to this statement. More specifically, a poor progression-free survival was observed for ERBB2 high, and ERBB2 low/BCAR4 positive, versus ERBB2 low/BCAR4 negative oestrogen receptor-α (ER)-positive breast cancers patients, who received first-line tamoxifen (54). The latter being an anti-oestrogen monotherapy for recurrent breast cancer that inhibits oestrogen-ER binding (55, 56). It should be mentioned that both ERBB2 (56-58), and BCAR4 (54, 59-61) are involved in tamoxifen resistance. These results are in line with the in vitro findings that ectopic expression of BCAR4 results in activation of ERBB2 signaling without overexpression of ERBB2 (54). These observations suggest that BCAR4 expression identifies a subgroup of ER-positive patients with activated ERBB2, but lacking ERBB2 overexpression, that might benefit from ERBB2-targeted therapy and anti-oestrogen therapy (54). The finding that ERBB2 activation status is more relevant than ERBB2 overexpression in the BCAR4 positive cell population, is somewhat reminiscent to the discussion that patients with tumors showing phosphorylated MET immunoreactivity are likely to be more susceptible to treatment with MET targeted therapies than patients showing MET immunoreactivity in general (62). Since MET TKIs are designed to reduce MET phosphorylation and consequent signaling activity (62), it is argued that rather phospho-MET, instead of membranous and/or cytoplasmic MET, immunoreactivity should be used as a selection criterion for the participation of clinical trials (chapter 7). As such, the proposed updated scoring system should ideally also account for phospho-MET immunoreactivity. In short, to further improve the proposed CD (chapters 4, 5, and 7), cytoplasmic and phospho-MET immunoreactivity should be incorporated alongside membranous MET immunoreactivity (full-length MET or MET-EC-) in future scoring systems and survival analyses. Does MET ectodomain shedding have an impact on the use of targeted therapies in OSCC? In chapter 3, it was established that D1C2 and CVD13 detected MET C-terminal fragments under reducing conditions that are the result of proteolysis (63), more specifically caspase cleavage (64, 65), ectodomain shedding (66), and RIPPing (67). Since ectodomain shedding might have an impact on the use of MET targeted therapies (moAbs and/or TKIs), it was investigated whether this process occurs 8
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