ABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Animals , Antibodies, Monoclonal/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 , 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 AssaysABSTRACT
The authors explored the relevance of research on change blindness to eyewitness identification and testimony under intentional and incidental memory conditions. Participants (N = 80, 40 men and 40 women) viewed a video enactment of a burglary in which the identity of the burglar changed at the halfway point of the film. Half of participants were briefed to remember the content, and the other half were not. All were tested for the recall of the content, awareness of the change, and ability to identify either or both of the burglars. Some 61% of participants did not notice the identity change. Rates of detection were significantly higher in participants in the intentional condition, who also recalled significantly more detail from the film. Awareness of change was also significantly related to content recall scores and accuracy of identification of both burglars. The results illustrate the interrelation between the eyewitness and change blindness literatures.
