Inhibiting receptor tyrosine kinase AXL with small molecule inhibitor BMS-777607 reduces glioblastoma growth, migration, and invasion in vitro and in vivo.

Julia Onken,Melina Nieminen,Frank Heppner,Xi Bai,Sören Korsing,Robert Torka,Axel Ullrich,Peter Vajkoczy,Josefine Radke,Irina Krementeskaia

doi:10.18632/oncotarget.7130

Julia Onken, Melina Nieminen + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.7130

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Abstract

PurposeReceptor tyrosine kinase AXL (RTK-AXL) is regarded as suitable target in glioma therapy. Here we evaluate the anti-tumoral effect of small molecule inhibitor BMS-777607 targeting RTK-AXL in a preclinical glioma model and provide evidence that RTK-AXL is expressed and phosphorylated in primary and recurrent glioblastoma multiforme (GBM).Experimental designWe studied the impact of BMS-777607 targeting RTK-AXL in GBM models in vitro and in vivo utilizing glioma cells SF126 and U118MG. Impact on proliferation, apoptosis and angiogenesis was investigated by immunohistochemistry (IHC) and functional assays in vitro and in vivo. Tumor growth was assessed with MRI. Human GBM tissue was analyzed in terms of RTK-AXL phosphorylation by immunoprecipitation and immunohistochemistry.ResultsBMS-777607 displayed various anti-cancer effects dependent on increased apoptosis, decreased proliferation and migration in vitro and ex vivo in SF126 and U118 GBM cells. In vivo we observed a 56% tumor volume reduction in SF126 xenografts and remission in U118MG xenografts of more than 91%. The tube formation assay confirmed the anti-angiogenic effect of BMS-777607, which became also apparent in tumor xenografts. IHC of human GBM tissue localized phosphorylated RTK-AXL in hypercellular tumor regions, the migratory front of tumor cells in pseudo-palisades, and in vascular proliferates within the tumor. We further proved RTK-AXL phosphorylation in primary and recurrent disease state.ConclusionCollectively, these data strongly suggest that targeting RTK-AXL with BMS-777607 could represent a novel and potent regimen for the treatment of primary and recurrent GBM.

Highlights

Malignant gliomas are the most common and most aggressive brain tumors due to their highly invasive growth pattern, proliferative capacities and heterogeneity [1]
The expression of receptor tyrosine kinase AXL (RTK-AXL) in U118MG and SF126 cells in vitro and in vivo was confirmed by immunofluorescence staining of adherent cells (Figure 1A) and intracranial tumor tissue (Figure 1B)
U118MG compared to SF126 (Figure 1C, left image)

Summary

Introduction

Malignant gliomas are the most common and most aggressive brain tumors due to their highly invasive growth pattern, proliferative capacities and heterogeneity [1]. The receptor tyrosine kinase AXL (RTK-AXL) displays a new promising target in glioma therapy [5]. RTK-AXL/Gas signaling is in charge of regulating survival, proliferation, and migration in different types of cells in vitro, including tumor-derived epithelial, mesenchymal, and hematopoietic cell lines [6,7,8]. RTK-AXL/Gas overexpression has been described in a multitude of human cancers, including GBM, colon, breast, prostate, thyroid, lung cancer, and malignant melanoma [6, 7, 9]. It has been shown that overexpression of RTK-AXL and Gas in GBM tissue is associated with reduced time to progression and overall survival in these patients [10, 11]. Anti-apoptotic Bcl-2 family members (e.g., Bcl-2) are unregulated while pro-apoptotic family members (e.g., BAD) are inactivated [7, 13, 14]

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