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

• Published in: Oncogene 2015-10, Vol.34 (41), p.5277-5287
• Main Authors: Greenall, S A, Donoghue, J F, Van Sinderen, M, Dubljevic, V, Budiman, S, Devlin, M, Street, I, Adams, T E, Johns, T G
• Format: Article
• Language: English
• Subjects: 13; 631/67/1922; 64/60; 96/31; 96/35; 96/95; Analgesics - pharmacology; Animals; Antibodies, Monoclonal - pharmacology; Antitumor activity; Apoptosis; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain tumors; Cancer; Care and treatment; Cell Biology; Cell Line, Tumor; Development and progression; Epidermal growth factor; Female; Focal adhesion kinase; Focal Adhesion Kinase 1 - metabolism; Gene expression; Genetic aspects; Glioma; Glioma - drug therapy; Glioma - genetics; Glioma - metabolism; Glioma cells; Gliomas; Health aspects; Human Genetics; Indoles - pharmacology; Internal Medicine; Kinases; Medicine; Medicine & Public Health; Mice, Inbred BALB C; Monoclonal antibodies; Mutants; Mutation; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Oncology; original-article; 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; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - physiology; Signal Transduction; Targeted cancer therapy; Transcriptional Activation; Tyrosine; Xenograft Model Antitumor Assays
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.448

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.