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

Abstract

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

Inhibition of HDAC1/2 Along with TRAP1 Causes Synthetic Lethality in Glioblastoma Model Systems

“…The elucidation of more durable treatment modalities, including novel drug combination therapies, for the treatment of GBM remains one of the highest priorities [ 2 , 3 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. The present drug combination, involving gamitrinib and HDAC inhibitors, appears to be effective against a broad range of different GBM model systems, suggesting potentially broad applicability, particularly with regards to heterogeneity.…”

The role of p-Stat3 Y705 immunohistochemistry in glioblastoma prognosis

“…Through its expression, it promotes the activation of neoangiogenesis in glioblastoma, highlighting the role of Stat3 in cellular adaptation in extreme conditions [7, 21, 26]. Furthermore, Stat3 is an activator of the epithelial-mesenchymal transition (EMT) process in glioblastoma, both through TGFβ and HIF-1α, thus enhancing tumour high motility, invasiveness and chemo resistance, which could account for the positivity of cells at the invasion front [27–30]. HIF-1 and Stat3 can also activate the transcription of zinc finger transcription factor (ZEB) proteins, especially ZEB1, which promotes EMT, migration and invasion [31, 32].…”

Overcoming Compensatory Mechanisms toward Chronic Drug Administration to Ensure Long-Term, Sustainable Beneficial Effects

“…Simultaneous inhibition of MET and one of these upregulated proteins promotes cell death and inhibits cell proliferation in resistant cells. 27 A combination of three drugs, cetuximab, trastuzumab (an anti-HER2 mAb), and osimertinib, prevents the onset of resistance to osimertinib. 28 However, these combinations may be associated with the development of multiple drug resistance.…”