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

Oncogene volume 34, pages 5277–5287 (2015)Cite this article

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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.

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Acknowledgements

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.

Author Contributions

SAG, JFD, TEA and TGJ conceived the idea and designed the experiments; SAG, JFD, MVS, VD and SB performed the experiments; SAG, JFD, MVS, VD, MD, IS, TEA and TGJ analyzed and interpreted the data; SAG, JFD, MD, IS, TEA and TGJ wrote and revised the manuscript; MD and IS provided reagents; and TEA and TGJ supervised the study.

Author information

Author notes

  1. M Van Sinderen

    Present address: 9Current address: Centre for Reproductive Health, MIMR-PHI Institute of Medical Research, Clayton, VIC, Australia and Monash University, Clayton, VIC, Australia.,

  2. V Dubljevic

    Present address: 10Current address: Patrys, Level 6, Equitable House, Melbourne, VIC, Australia.,

  3. S A Greenall and J F Donoghue: These authors contributed equally to this study.

  4. T E Adams and T G Johns: These laboratories contributed equally to this study.

Authors and Affiliations

  1. Oncogenic Signalling Laboratory and Brain Cancer Discovery Collaborative, Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Clayton, VIC, Australia

    S A Greenall, J F Donoghue, M Van Sinderen, V Dubljevic, S Budiman & T G Johns

  2. Monash University, Clayton, VIC, Australia

    S A Greenall, J F Donoghue, M Van Sinderen, V Dubljevic, S Budiman & T G Johns

  3. Division of Materials Science and Engineering, Commonwealth Scientific and Industrial Research Organisation, Parkville, VIC, Australia

    S A Greenall & T E Adams

  4. Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, Australia

    M Devlin

  5. CRC for Cancer Therapeutics, Bundoora, VIC, Australia

    I Street

  6. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia

    I Street

  7. Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia

    I Street

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  1. S A Greenall
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Corresponding author

Correspondence to T G Johns.

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Competing interests

MD and IS are inventors listed on patent applications for FAK inhibitors. TGJ has received project funding from Amgen.

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Greenall, S., Donoghue, J., Van Sinderen, M. et al. EGFRvIII-mediated transactivation of receptor tyrosine kinases in glioma: mechanism and therapeutic implications. Oncogene 34, 5277–5287 (2015). https://doi.org/10.1038/onc.2014.448

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