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

被引：42

作者：

Greenall, S. A. ^{[1
,2
,3
,4
]}

Donoghue, J. F. ^{[1
,2
,3
]}

Van Sinderen, M. ^{[1
,2
,3
]}

Dubljevic, V. ^{[1
,2
,3
]}

Budiman, S. ^{[1
,2
,3
]}

Devlin, M. ^{[5
]}

Street, I. ^{[6
,7
,8
]}

Adams, T. E. ^{[4
]}

Johns, T. G. ^{[1
,2
,3
]}

机构：

[1] MIMR PHI Inst Med Res, Ctr Canc Res, Oncogen Signalling Lab, Clayton, Vic 3168, Australia

[2] MIMR PHI Inst Med Res, Ctr Canc Res, Brain Canc Discovery Collaborat, Clayton, Vic 3168, Australia

[3] Monash Univ, Clayton, Vic, Australia

[4] CSIRO, Div Mat Sci & Engn, Parkville, Vic, Australia

[5] Peter MacCallum Canc Ctr, East Melbourne, Vic, Australia

[6] CRC Canc Therapeut, Bundoora, Vic, Australia

[7] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Parkville, Vic 3050, Australia

[8] Univ Melbourne, Dept Med Biol, Parkville, Vic 3052, Australia

来源：

ONCOGENE | 2015年 / 34卷 / 41期

基金：

英国医学研究理事会;

关键词：

GROWTH-FACTOR RECEPTOR; FOCAL ADHESION KINASE; DOMAIN BINDING-SITE; CELLS; GLIOBLASTOMAS; AMPLIFICATION; ACTIVATION; RESISTANCE; INHIBITORS; MUTATIONS;

D O I：

10.1038/onc.2014.448

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：5277 / 5287

页数：11

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