EGFRvIII-mediated transactivation of receptor tyrosine kinases in glioma: mechanism and therapeutic implications

Sameer A Greenall, Jacqueline Faye Donoghue, Michelle Leigh Van Sinderen, Valentina Dubljevic, Stephanie Elizabeth Budiman, Mark Devlin, Ian Philip Street, Timothy E Adams, Terrance Grant Johns

Research output: Contribution to journalArticleResearchpeer-review

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 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.Oncogene advance online publication, 9 February 2015; doi:10.1038/onc.2014.448.
Original languageEnglish
Pages (from-to)5277 - 5287
Number of pages11
JournalOncogene
Volume34
Issue number41
DOIs
Publication statusPublished - 2015

Cite this

Greenall, Sameer A ; Donoghue, Jacqueline Faye ; Van Sinderen, Michelle Leigh ; Dubljevic, Valentina ; Budiman, Stephanie Elizabeth ; Devlin, Mark ; Street, Ian Philip ; Adams, Timothy E ; Johns, Terrance Grant. / EGFRvIII-mediated transactivation of receptor tyrosine kinases in glioma: mechanism and therapeutic implications. In: Oncogene. 2015 ; Vol. 34, No. 41. pp. 5277 - 5287.
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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 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.Oncogene advance online publication, 9 February 2015; doi:10.1038/onc.2014.448.",
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Greenall, SA, Donoghue, JF, Van Sinderen, ML, Dubljevic, V, Budiman, SE, Devlin, M, Street, IP, Adams, TE & Johns, TG 2015, 'EGFRvIII-mediated transactivation of receptor tyrosine kinases in glioma: mechanism and therapeutic implications' Oncogene, vol. 34, no. 41, pp. 5277 - 5287. https://doi.org/10.1038/onc.2014.448

EGFRvIII-mediated transactivation of receptor tyrosine kinases in glioma: mechanism and therapeutic implications. / Greenall, Sameer A; Donoghue, Jacqueline Faye; Van Sinderen, Michelle Leigh; Dubljevic, Valentina; Budiman, Stephanie Elizabeth; Devlin, Mark; Street, Ian Philip; Adams, Timothy E; Johns, Terrance Grant.

In: Oncogene, Vol. 34, No. 41, 2015, p. 5277 - 5287.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Donoghue, Jacqueline Faye

AU - Van Sinderen, Michelle Leigh

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AU - Budiman, Stephanie Elizabeth

AU - Devlin, Mark

AU - Street, Ian Philip

AU - Adams, Timothy E

AU - Johns, Terrance Grant

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