EGFRvIII-mediated transactivation of receptor tyrosine kinases in glioma: mechanism and therapeutic implications
SA Greenall, JF Donoghue, M Van Sinderen, V Dubljevic, S Budiman, M Devlin, I Street, TE Adams, TG Johns
Oncogene | NATURE PUBLISHING GROUP | Published : 2015
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..View full abstract
Awarded by Victorian Cancer Agency Early Career Seed Grant
Awarded by National Health and Medical Research Council Project
We acknowledge the facilities and scientific and technical assistance of the Histology Facility, Microimaging facility and Monash Animal Services, at MIMR-PHI Institute of Medical Research. We thank Dr D Dadley-Moore for editing the manuscript. SAG is funded by a Commonwealth Scientific and Industrial Research Organisation (CSIRO) OCE Postdoctoral Fellowship. JFD is funded by a Cure Cancer Australia Foundation postdoctoral fellowship and a Victorian Cancer Agency Early Career Seed Grant (ECSG1108). TGJ is funded by National Health and Medical Research Council Project Grants 1028552 and 1012020, the Victorian Government's Operational and Infrastructure Support Program and the Cure Brain Cancer Foundation. This work was supported by the CRC for Cancer Therapeutics, an initiative of the Australian Government. Rilotumumab and motesanib must be obtained through an MTA. Rilotumumab, panitumumab and motesanib were provided by Amgen (rilotumumab and motesanib through an MTA); and dacomitinib was provided by Pfizer.