title: EGFRvIII-mediated transactivation of receptor tyrosine kinases in glioma: mechanism and therapeutic implications.
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.
authors: Oncogenic Signalling Laboratory and Brain Cancer Discovery Collaborative, Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Clayton, VIC, Australia.|Monash University, Clayton, VIC, Australia.|Division of Materials Science and Engineering, Commonwealth Scientific and Industrial Research Organisation, Parkville, VIC, Australia.
authors: S A
authors: SA
authors: Greenall
authors: Oncogenic Signalling Laboratory and Brain Cancer Discovery Collaborative, Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Clayton, VIC, Australia.|Monash University, Clayton, VIC, Australia.
authors: J F
authors: JF
authors: Donoghue
authors: Oncogenic Signalling Laboratory and Brain Cancer Discovery Collaborative, Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Clayton, VIC, Australia.|Monash University, Clayton, VIC, Australia.
authors: M
authors: M
authors: Van Sinderen
authors: Oncogenic Signalling Laboratory and Brain Cancer Discovery Collaborative, Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Clayton, VIC, Australia.|Monash University, Clayton, VIC, Australia.
authors: V
authors: V
authors: Dubljevic
authors: Oncogenic Signalling Laboratory and Brain Cancer Discovery Collaborative, Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Clayton, VIC, Australia.|Monash University, Clayton, VIC, Australia.
authors: S
authors: S
authors: Budiman
authors: Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, Australia.
authors: M
authors: M
authors: Devlin
authors: CRC for Cancer Therapeutics, Bundoora, VIC, Australia.|The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors: I
authors: I
authors: Street
authors: Division of Materials Science and Engineering, Commonwealth Scientific and Industrial Research Organisation, Parkville, VIC, Australia.
authors: T E
authors: TE
authors: Adams
authors: Oncogenic Signalling Laboratory and Brain Cancer Discovery Collaborative, Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Clayton, VIC, Australia.|Monash University, Clayton, VIC, Australia.
authors: T G
authors: TG
authors: Johns
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D008807:Mice, Inbred BALB C; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D009841:Oligonucleotides; D000077544:Panitumumab; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000700:Analgesics; D000911:Antibodies, Monoclonal; D007211:Indoles; D009841:Oligonucleotides; D047428:Protein Kinase Inhibitors; C410723:epidermal growth factor receptor VIII; D009536:Niacinamide; D000077544:Panitumumab; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C519562:imetelstat