Discovery and Therapeutic Exploitation of Mechanisms of Resistance to MET Inhibitors in Glioblastoma

Clin Cancer Res. 2019 Jan 15;25(2):663-673. doi: 10.1158/1078-0432.CCR-18-0926. Epub 2018 Sep 10.


Purpose: Glioblastoma (GBM) is the most common and most lethal primary malignant brain tumor. The receptor tyrosine kinase MET is frequently upregulated or overactivated in GBM. Although clinically applicable MET inhibitors have been developed, resistance to single modality anti-MET drugs frequently occurs, rendering these agents ineffective. We aimed to determine the mechanisms of MET inhibitor resistance in GBM and use the acquired information to develop novel therapeutic approaches to overcome resistance.Experimental Design: We investigated two clinically applicable MET inhibitors: crizotinib, an ATP-competitive small molecule inhibitor of MET, and onartuzumab, a monovalent monoclonal antibody that binds to the extracellular domain of the MET receptor. We developed new MET inhibitor-resistant cells lines and animal models and used reverse phase protein arrays (RPPA) and functional assays to uncover the compensatory pathways in MET inhibitor-resistant GBM.

Results: We identified critical proteins that were altered in MET inhibitor-resistant GBM including mTOR, FGFR1, EGFR, STAT3, and COX-2. Simultaneous inhibition of MET and one of these upregulated proteins led to increased cell death and inhibition of cell proliferation in resistant cells compared with either agent alone. In addition, in vivo treatment of mice bearing MET-resistant orthotopic xenografts with COX-2 or FGFR pharmacological inhibitors in combination with MET inhibitor restored sensitivity to MET inhibition and significantly inhibited tumor growth.

Conclusions: These data uncover the molecular basis of adaptive resistance to MET inhibitors and identify new FDA-approved multidrug therapeutic combinations that can overcome resistance.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Brain Neoplasms
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Drug Resistance, Neoplasm* / genetics
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Glioblastoma / drug therapy
  • Glioblastoma / genetics
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Mice
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / metabolism
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • MTOR protein, human
  • ErbB Receptors
  • FGFR1 protein, human
  • Proto-Oncogene Proteins c-met
  • Receptor, Fibroblast Growth Factor, Type 1
  • TOR Serine-Threonine Kinases
  • onartuzumab