Genomic profiling of a Hepatocyte growth factor-dependent signature for MET-targeted therapy in glioblastoma

J Transl Med. 2015 Sep 17;13:306. doi: 10.1186/s12967-015-0667-x.


Background: Constitutive MET signaling promotes invasiveness in most primary and recurrent GBM. However, deployment of available MET-targeting agents is confounded by lack of effective biomarkers for selecting suitable patients for treatment. Because endogenous HGF overexpression often causes autocrine MET activation, and also indicates sensitivity to MET inhibitors, we investigated whether it drives the expression of distinct genes which could serve as a signature indicating vulnerability to MET-targeted therapy in GBM.

Methods: Interrogation of genomic data from TCGA GBM (Student's t test, GBM patients with high and low HGF expression, p ≤ 0.00001) referenced against patient-derived xenograft (PDX) models (Student's t test, sensitive vs. insensitive models, p ≤ 0.005) was used to identify the HGF-dependent signature. Genomic analysis of GBM xenograft models using both human and mouse gene expression microarrays (Student's t test, treated vs. vehicle tumors, p ≤ 0.01) were performed to elucidate the tumor and microenvironment cross talk. A PDX model with EGFR(amp) was tested for MET activation as a mechanism of erlotinib resistance.

Results: We identified a group of 20 genes highly associated with HGF overexpression in GBM and were up- or down-regulated only in tumors sensitive to MET inhibitor. The MET inhibitors regulate tumor (human) and host (mouse) cells within the tumor via distinct molecular processes, but overall impede tumor growth by inhibiting cell cycle progression. EGFR (amp) tumors undergo erlotinib resistance responded to a combination of MET and EGFR inhibitors.

Conclusions: Combining TCGA primary tumor datasets (human) and xenograft tumor model datasets (human tumor grown in mice) using therapeutic efficacy as an endpoint may serve as a useful approach to discover and develop molecular signatures as therapeutic biomarkers for targeted therapy. The HGF dependent signature may serve as a candidate predictive signature for patient enrollment in clinical trials using MET inhibitors. Human and mouse microarrays maybe used to dissect the tumor-host interactions. Targeting MET in EGFR (amp) GBM may delay the acquired resistance developed during treatment with erlotinib.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autocrine Communication / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • ErbB Receptors / metabolism
  • Erlotinib Hydrochloride / pharmacology
  • Erlotinib Hydrochloride / therapeutic use
  • Gene Expression Profiling*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genomics
  • Glioblastoma / drug therapy*
  • Glioblastoma / genetics*
  • Glioblastoma / pathology
  • Hepatocyte Growth Factor / metabolism*
  • Humans
  • Mice
  • Models, Biological
  • Molecular Targeted Therapy*
  • Neoplasm Invasiveness
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / metabolism
  • Treatment Outcome
  • Xenograft Model Antitumor Assays


  • HGF protein, human
  • Protein Kinase Inhibitors
  • Hepatocyte Growth Factor
  • Erlotinib Hydrochloride
  • ErbB Receptors
  • Proto-Oncogene Proteins c-met