Implications of Mutant Epidermal Growth Factor Variant III in Brain Tumor Development and Novel Targeted Therapies

Abstract

The mutant epidermal growth factor receptor variant III (EGFRvIII) oncogene has attracted much attention due to its critical functions in primary brain cancer development, treatment resistance and disease relapse. The EGFRvIII mutant is frequently overexpressed during brain cancer initiation and progression in conjunction with the wild-type EGFR amplification while no expression level of its truncated receptor is detected in normal brain tissue specimens and any distant tissues. The constitutively activated EGFRvIII mutant can substantially contribute in cooperation with other receptor tyrosine kinases, including wild-type EGFR, to the sustained growth, migration and local metastases of brain cancer cells and resistance to current therapies. Therefore, the truncated EGFRvIII mutant represents a therapeutic target of great clinical interest for developing new effective treatments against primary brain tumors. In this chapter, we summarize the recent advancements on the characterization of key functions supplied by the EGFRvIII mutant and wild-type EGFR in brain tumor development and the most important findings about the novel therapeutic strategies developed for their effective molecular targeting. The emphasis is on the specific roles played by the EGFRvIII mutant and its cooperative interactions with wild-type EGFR in brain tumor cells, treatment resistance and disease relapse. The implications of targeting the EGFRvIII mutant and/or wild-type EGFR to develop novel combination therapies for improving the current treatments against aggressive and recurrent medulloblastomas and glioblastoma multiforme are also discussed.