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

S A Greenall; J F Donoghue; M Van Sinderen; V Dubljevic; S Budiman; M Devlin; I Street; T E Adams; T G Johns

doi:10.1038/onc.2014.448

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

Oncogene. 2015 Oct 8;34(41):5277-87. doi: 10.1038/onc.2014.448. Epub 2015 Feb 9.

Authors

S A Greenall^{1

2

3}, J F Donoghue^{1

2}, M Van Sinderen^{1

2}, V Dubljevic^{1

2}, S Budiman^{1

2}, M Devlin⁴, I Street^{5

6

7}, T E Adams³, T G Johns^{1

2}

Affiliations

¹ Oncogenic Signalling Laboratory and Brain Cancer Discovery Collaborative, Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Clayton, VIC, Australia.
² Monash University, Clayton, VIC, Australia.
³ Division of Materials Science and Engineering, Commonwealth Scientific and Industrial Research Organisation, Parkville, VIC, Australia.
⁴ Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, Australia.
⁵ CRC for Cancer Therapeutics, Bundoora, VIC, Australia.
⁶ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
⁷ Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.

PMID: 25659577
DOI: 10.1038/onc.2014.448

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Analgesics / pharmacology
Animals
Antibodies, Monoclonal / pharmacology
Apoptosis
Brain Neoplasms / drug therapy
Brain Neoplasms / genetics
Brain Neoplasms / metabolism*
Cell Line, Tumor
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / physiology*
Female
Focal Adhesion Kinase 1 / metabolism
Glioma / drug therapy
Glioma / genetics
Glioma / metabolism*
Indoles / pharmacology
Mice, Inbred BALB C
Niacinamide / analogs & derivatives
Niacinamide / pharmacology
Oligonucleotides
Panitumumab
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-met / genetics
Proto-Oncogene Proteins c-met / metabolism
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
Receptor Protein-Tyrosine Kinases / metabolism
Signal Transduction
Transcriptional Activation*
Xenograft Model Antitumor Assays

Substances

Analgesics
Antibodies, Monoclonal
Indoles
Oligonucleotides
Protein Kinase Inhibitors
epidermal growth factor receptor VIII
Niacinamide
Panitumumab
ErbB Receptors
MET protein, human
Proto-Oncogene Proteins c-met
Receptor Protein-Tyrosine Kinases
Focal Adhesion Kinase 1
PTK2 protein, human
imetelstat