A combination of tyrosine kinase inhibitors, crizotinib and dasatinib for the treatment of glioblastoma multiforme.

Hayley Nehoff,Melanie J Mcconnell,Neha N Parayath,Sebastien Taurin,Khaled Greish

doi:10.18632/oncotarget.5698

Hayley Nehoff, Melanie J Mcconnell + Show 3 more

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https://doi.org/10.18632/oncotarget.5698

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Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Despite the advances in surgery, radiotherapy and chemotherapy, patient survival averages only 14.6 months. In most GBM tumors, tyrosine kinases show increased activity and/or expression and actively contribute to the development, recurrence and onset of treatment resistance; making their inhibition an appealing therapeutic strategy. We compared the cytotoxicity of 12 tyrosine kinase inhibitors in vitro. A combination of crizotinib and dasatinib emerged as the most cytotoxic across established and primary human GBM cell lines. The combination treatment induced apoptotic cell death and polyploidy. Furthermore, the combination treatment led to the altered expression and localization of several tyrosine kinase receptors such as Met and EGFR and downstream effectors as such as SRC. Furthermore, the combination treatment reduced the migration and invasion of GBM cells and prevented endothelial cell tube formation in vitro. Overall, our study demonstrated the broad specificity of a combination of crizotinib and dasatinib across multiple GBM cell lines. These findings provide insight into the development of alternative therapy for the treatment of GBM.

Highlights

Glioblastoma multiforme (GBM), a grade IV astrocytoma, is the most frequent and aggressive malignant primary brain tumor with a 5-year survival rate of 5% [1]
We assessed the effect of several tyrosine kinase inhibitors (TKIs) including sorafenib, nilotinib, sunitinib, imatinib, gefitinib, lapatinib, PD-173074, selumetinib, tofacitinib, pazopanib, dasatinib and crizotinib on the cellular viability of four established GBM cell lines (Table 1)
We optimized the concentrations for both drugs to obtain a potent effect across all etablished and primary GBM cell lines used in this study and proceeded with 0.2 μM of dasatinib and 4 μM of crizotinib

Summary

Introduction

Glioblastoma multiforme (GBM), a grade IV astrocytoma, is the most frequent and aggressive malignant primary brain tumor with a 5-year survival rate of 5% [1]. The standard treatment for GBM involves surgical resection and radiotherapy with concomitant and adjuvant temozolomide administration [6]. Despite the three-pronged treatment strategy, relapse is universal. The limited efficacy of the current treatments is partially a consequence of the heterogeneity of the tumour cell population. GBM is classified into four subtypes, the classical, mesenchymal, proneural and neural subtypes all characterised by distinct transcriptional profiles [7]. The subtypes are associated with the amplification and/ or mutation of several receptor tyrosine kinases (RTKs) such as the hepatocyte growth factor receptor (Met), the platelet-derived growth factor receptor (PDGFR)-α and epidermal growth factor receptor (EGFR) in the mesenchymal, proneural and classical subtypes, respectively [7]. Recent studies have confirmed tumours harboring more than one subtype [8, 9]

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