EGFR^vIII: An Oncogene with Ambiguous Role

Epidermal growth factor receptor variant III (EGFR^vIII) seems to constitute the perfect therapeutic target for glioblastoma (GB), as it is specifically present on up to 28-30% of GB cells. In case of other tumor types, expression and possible role of this oncogene still remain controversial. In spite of EGFR^vIII mechanism of action being crucial for the design of small active anticancer molecules and immunotherapies, i.e., CAR-T technology, it is yet to be precisely defined. EGFR^vIII is known to be resistant to degradation, but it is still unclear whether it heterodimerizes with EGF-activated wild-type EGFR (EGFR^WT) or homodimerizes (including covalent homodimerization). Constitutive kinase activity of this mutated receptor is relatively low, and some researchers even claim that a nuclear, but not a membrane function, is crucial for its activity. Based on the analyses of recurrent tumors that are often lacking EGFR^vIII expression despite its initial presence in corresponding primary foci, this oncogene is suggested to play a marginal role during later stages of carcinogenesis, while even in primary tumors EGFR^vIII expression is detected only in a small percentage of tumor cells, undermining the rationality of EGFR^vIII-targeting therapies. On the other hand, EGFR^vIII-positive cells are resistant to apoptosis, more invasive, and characterized with enhanced proliferation rate. Moreover, expression of this oncogenic receptor was also postulated to be a marker of cancer stem cells. Opinions regarding the role that EGFR^vIII plays in tumorigenesis and for tumor aggressiveness are clearly contradictory and, therefore, it is crucial not only to determine its mechanism of action, but also to unambiguously define its role at early and advanced cancer stages.