title: Gene expression profile identifies tyrosine kinase c-Met as a targetable mediator of antiangiogenic therapy resistance.
abstract: OBJECTIVE
  To identify mediators of glioblastoma antiangiogenic therapy resistance and target these mediators in xenografts.
  
  
  METHODS
  We conducted microarray analysis comparing bevacizumab-resistant glioblastomas (BRG) with pretreatment tumors from the same patients. We established novel xenograft models of antiangiogenic therapy resistance to target candidate resistance mediator(s).
  
  
  RESULTS
  BRG microarray analysis revealed upregulation versus pretreatment of receptor tyrosine kinase c-Met, which underwent further investigation because of its prior biologic plausibility as a bevacizumab resistance mediator. BRGs exhibited increased hypoxia versus pretreatment in a manner correlating with their c-Met upregulation, increased c-Met phosphorylation, and increased phosphorylation of c-Met-activated focal adhesion kinase and STAT3. We developed 2 novel xenograft models of antiangiogenic therapy resistance. In the first model, serial bevacizumab treatment of an initially responsive xenograft generated a xenograft with acquired bevacizumab resistance, which exhibited upregulated c-Met expression versus pretreatment. In the second model, a BRG-derived xenograft maintained refractoriness to the MRI tumor vasculature alterations and survival-promoting effects of bevacizumab. Growth of this BRG-derived xenograft was inhibited by a c-Met inhibitor. Transducing these xenograft cells with c-Met short hairpin RNA inhibited their invasion and survival in hypoxia, disrupted their mesenchymal morphology, and converted them from bevacizumab-resistant to bevacizumab-responsive. Engineering bevacizumab-responsive cells to express constitutively active c-Met caused these cells to form bevacizumab-resistant xenografts.
  
  
  CONCLUSIONS
  These findings support the role of c-Met in survival in hypoxia and invasion, features associated with antiangiogenic therapy resistance, and growth and therapeutic resistance of xenografts resistant to antiangiogenic therapy. Therapeutically targeting c-Met could prevent or overcome antiangiogenic therapy resistance.
authors: Department of Neurological Surgery, University of California at San Francisco, San Francisco, CA 94158, USA.
authors: Arman
authors: A
authors: Jahangiri
authors: Michael
authors: M
authors: De Lay
authors: Liane M
authors: LM
authors: Miller
authors: W Shawn
authors: WS
authors: Carbonell
authors: Yu-Long
authors: YL
authors: Hu
authors: Kan
authors: K
authors: Lu
authors: Maxwell W
authors: MW
authors: Tom
authors: Jesse
authors: J
authors: Paquette
authors: Taku A
authors: TA
authors: Tokuyasu
authors: Sean
authors: S
authors: Tsao
authors: Roxanne
authors: R
authors: Marshall
authors: Arie
authors: A
authors: Perry
authors: Kirsten M
authors: KM
authors: Bjorgan
authors: Myriam M
authors: MM
authors: Chaumeil
authors: Sabrina M
authors: SM
authors: Ronen
authors: Gabriele
authors: G
authors: Bergers
authors: Manish K
authors: MK
authors: Aghi
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D034622:RNA Interference; D059467:Transcriptome; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D019859:Proto-Oncogene Proteins c-met