title: Hepatocyte growth factor sensitizes brain tumors to c-MET kinase inhibition.
abstract: OBJECTIVE
  The receptor tyrosine kinase (RTK) c-MET and its ligand hepatocyte growth factor (HGF) are deregulated and promote malignancy in cancer and brain tumors. Consequently, clinically applicable c-MET inhibitors have been developed. The purpose of this study was to investigate the not-well-known molecular determinants that predict responsiveness to c-MET inhibitors and to explore new strategies for improving inhibitor efficacy in brain tumors.
  
  
  METHODS
  We investigated the molecular factors and pathway activation signatures that determine sensitivity to c-MET inhibitors in a panel of glioblastoma and medulloblastoma cells, glioblastoma stem cells, and established cell line-derived xenografts using functional assays, reverse protein microarrays, and in vivo tumor volume measurements, but validation with animal survival analyses remains to be done. We also explored new approaches for improving the efficacy of the inhibitors in vitro and in vivo.
  
  
  RESULTS
  We found that HGF coexpression is a key predictor of response to c-MET inhibition among the examined factors and identified an ERK/JAK/p53 pathway activation signature that differentiates c-MET inhibition in responsive and nonresponsive cells. Surprisingly, we also found that short pretreatment of cells and tumors with exogenous HGF moderately but statistically significantly enhanced the antitumor effects of c-MET inhibition. We observed a similar ligand-induced sensitization effect to an EGF receptor small-molecule kinase inhibitor.
  
  
  CONCLUSIONS
  These findings allow the identification of a subset of patients that will be responsive to c-MET inhibition and propose ligand pretreatment as a potential new strategy for improving the anticancer efficacy of RTK inhibitors.
authors: Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia 22908, USA. yz5h@virginia.edu
authors: Ying
authors: Y
authors: Zhang
authors: Kaitlyn E
authors: KE
authors: Farenholtz
authors: Yanzhi
authors: Y
authors: Yang
authors: Fadila
authors: F
authors: Guessous
authors: Charles G
authors: CG
authors: Dipierro
authors: Valerie S
authors: VS
authors: Calvert
authors: Jianghong
authors: J
authors: Deng
authors: David
authors: D
authors: Schiff
authors: Wenjun
authors: W
authors: Xin
authors: Jae K
authors: JK
authors: Lee
authors: Benjamin
authors: B
authors: Purow
authors: James
authors: J
authors: Christensen
authors: Emanuel
authors: E
authors: Petricoin
authors: Roger
authors: R
authors: Abounader
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met
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