CSIG-07EGFRvIII MEDIATED TRANSACTIVATION OF RECEPTOR TYROSINE KINASES IN GLIOMA: MECHANISM AND THERAPEUTIC IMPLICATIONS

Abstract

A truncation mutant of the epidermal growth factor receptor, EGFRvIII, is commonly expressed in glioma, an incurable brain cancer.EGFRvIII is tumorigenic, in part, through its transactivation of other receptor tyrosine kinases (RTKs). Preventing the effects of thistransactivation could form part of an effective therapy for glioma; however, the mechanism by which the transactivation occurs isunknown. Focusing on the RTK MET, we show that MET transactivation in U87MG human glioma cells in vitro is proportional toEGFRvIII activity and involves MET heterodimerization associated with a focal adhesion kinase (FAK) scaffold. The transactivationof certain other RTKs was, however, independent of FAK. Simultaneously targeting EGFRvIII (with panitumumab) and thetransactivated RTKs themselves (with motesanib) in an intracranial mouse model of glioma resulted in significantly greater survivalthan with either agent alone, indicating that cotargeting these RTKs has potent antitumor efficacy and providing a strategyfor treating EGFRvIII-expressing gliomas, which are usually refractory to treatment.Oncogene advance online publication, 9 February 2015; doi:10.1038/onc.2014.448INTRODUCTIONHigh-grade glioma (HGG), often simply called glioma, is amalignant brain tumor that is incurable because of its relativelyrefractory nature to the standard of care, which involves surgicalresection, radiotherapy and the chemotherapeutic temozolomide.Glioma has been classified into four distinct molecular subtypes,each characterized by a set of molecular traits.