Abstract
Better understanding of GBM signalling networks in-vivo would help develop more physiologically relevant ex vivo models to support therapeutic discovery. A "functional proteomics" screen was undertaken to measure the specific activity of a set of protein kinases in a two-step cell-free biochemical assay to define dominant kinase activities to identify potentially novel drug targets that may have been overlooked in studies interrogating GBM-derived cell lines. A dominant kinase activity derived from the tumour tissue, but not patient-derived GBM stem-like cell lines, was Bruton tyrosine kinase (BTK). We demonstrate that BTK is expressed in more than one cell type within GBM tissue; SOX2-positive cells, CD163-positive cells, CD68-positive cells, and an unidentified cell population which is SOX2-negative CD163-negative and/or CD68-negative. The data provide a strategy to better mimic GBM tissue ex vivo by reconstituting more physiologically heterogeneous cell co-culture models including BTK-positive/negative cancer and immune cells. These data also have implications for the design and/or interpretation of emerging clinical trials using BTK inhibitors because BTK expression within GBM tissue was linked to longer patient survival.
Highlights
Glioblastoma (GBM), a World Health Organization (WHO) grade IV astrocytoma, is the most common aggressive tumour originating in the brain (1)
We demonstrate that Bruton tyrosine kinase (BTK) is expressed in at least four cell types; SOX2positive cells, CD163-positive cells, CD68-positive cells, and a fourth cell population which is SOX2 negative, CD163 negative, and/or CD68 negative
This study identifies a novel relevance of BTK towards GBM molecular biology
Summary
Glioblastoma (GBM), a World Health Organization (WHO) grade IV astrocytoma, is the most common aggressive tumour originating in the brain (1). Median survival is less than 15 mo, even with surgery, radiotherapy and chemotherapy using the alkylating agent temozolomide (TMZ) (3, 4). Drug resistance, invasion of surrounding brain tissue, intratumoural heterogeneity, necrosis, and aggressive vascularization have all been implicated in the poor response of GBM to treatment (5, 6, 7, 8, 9, 10). Efforts to identify novel effective therapeutic targets have largely failed, with few drugs successfully translating from drug trials into standard clinical use, and no significant impact on patient survival (11, 12, 13). Bevacizumab, a VEGF monoclonal antibody (14, 15), in combination with TMZ and/or lomustine improves progression-free, but not overall survival (16, 17).
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