EGFRvIII-mediated transactivation of receptor tyrosine kinases in glioma: mechanism and therapeutic implications
AuthorGreenall, SA; Donoghue, JF; Van Sinderen, M; Dubljevic, V; Budiman, S; Devlin, M; Street, I; Adams, TE; Johns, TG
PublisherNATURE PUBLISHING GROUP
AffiliationMedical Biology (W.E.H.I.)
Obstetrics and Gynaecology
Sir Peter MacCallum Department of Oncology
Document TypeJournal Article
CitationsGreenall, S. A., Donoghue, J. F., Van Sinderen, M., Dubljevic, V., Budiman, S., Devlin, M., Street, I., Adams, T. E. & Johns, T. G. (2015). EGFRvIII-mediated transactivation of receptor tyrosine kinases in glioma: mechanism and therapeutic implications. ONCOGENE, 34 (41), pp.5277-5287. https://doi.org/10.1038/onc.2014.448.
Access StatusAccess this item via the Open Access location
Open Access URLhttp://dx.doi.org/10.1038/onc.2014.448
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 this transactivation could form part of an effective therapy for glioma; however, the mechanism by which the transactivation occurs is unknown. Focusing on the RTK MET, we show that MET transactivation in U87MG human glioma cells in vitro is proportional to EGFRvIII activity and involves MET heterodimerization associated with a focal adhesion kinase (FAK) scaffold. The transactivation of certain other RTKs was, however, independent of FAK. Simultaneously targeting EGFRvIII (with panitumumab) and the transactivated RTKs themselves (with motesanib) in an intracranial mouse model of glioma resulted in significantly greater survival than with either agent alone, indicating that cotargeting these RTKs has potent antitumor efficacy and providing a strategy for treating EGFRvIII-expressing gliomas, which are usually refractory to treatment.
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