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| Home > Publications database > A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma. |
| Journal Article | DKFZ-2021-01541 |
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2022
Oxford Univ. Press
Oxford
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Please use a persistent id in citations: doi:10.1093/neuonc/noab158
Abstract: Glioblastoma is the most common primary malignancy of the central nervous system with dismal prognosis. Genomic signatures classify isocitrate dehydrogenase 1 (IDH)-wildtype glioblastoma into three subtypes: proneural, mesenchymal and classical. Dasatinib, an inhibitor of proto-oncogene kinase Src (SRC), is one of many therapeutics which, despite promising preclinical results, has failed to improve overall survival in glioblastoma patients in clinical trials. We examined whether glioblastoma subtypes differ in their response to dasatinib and could hence be evaluated for patient enrichment strategies in clinical trials.We carried out in silico analyses on glioblastoma gene expression (TCGA) and single-cell RNA-Seq data. In addition, in vitro experiments using glioblastoma stem-like cells (GSCs) derived from primary patient tumors were performed, with complementary gene expression profiling and immunohistochemistry analysis of tumor samples.Patients with the mesenchymal subtype of glioblastoma showed higher SRC pathway activation based on gene expression profiling. Accordingly, mesenchymal GSCs were more sensitive to SRC inhibition by dasatinib compared to proneural and classical GSCs. Notably, SRC phosphorylation status did not predict response to dasatinib treatment. Furthermore, serpin peptidase inhibitor clade H member 1 (SERPINH1), a collagen related heat-shock protein associated with cancer progression, was shown to correlate with dasatinib response and with the mesenchymal subtype.This work highlights further molecular-based patient selection strategies in clinical trials and suggests the mesenchymal subtype as well as SERPINH1 to be associated with response to dasatinib. Our findings indicate that stratification based on gene expression subtyping should be considered in future dasatinib trials.
Keyword(s): Dasatinib ; Glioblastoma ; Glioblastoma stem-like cells ; SERPINH1 ; SRC
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