A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma

Abstract

Background 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. Methods 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. Results 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. Conclusion 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.

In Vitro Validation of the Therapeutic Potential of Dendrimer-Based Nanoformulations against Tumor Stem Cells

“…JHH520 cells were more sensitive to dasatinib or free siLyn treatment, in comparison with “Lyn-negative” NCH644 cells. As JHH520 models a mesenchymal glioblastoma, and although a comparison is made between two lines only, this data is supportive of recent reports that patients suffering from the mesenchymal glioblastoma subtype might benefit most from receiving dasatinib therapy [ 50 ]. Verification studies to assess the target septicity by using the genetic enforced suppression of Lyn in Lyn-positive cell models and comparison to phenotypes of isogenic controlled conditions under therapy exposure are warranted to make any statement on the adversity risk of the developed platform.…”

Anti-Survival Effect of SI306 and Its Derivatives on Human Glioblastoma Cells

“…With regard to CAS-1 cells, the reduction in cell viability is not related to Src activity and might be due to other mechanisms that deserve further investigation. However, the data demonstrates that Src phosphorylation status does not predict the drug sensitivity in agreement with a recent study reporting that patients with different GBM subtypes expressed similar levels of the unphosphorylated and phosphorylated Src [ 44 ]. In the present study, the different sensitivity of two GBM cells to the tested compounds could be related to their pharmacokinetic profile, but also to the fact that CAS-1 cells express EGFR-vIII while U87 cells express EGFR WT .…”

Propofol enhances stem-like properties of glioma via GABAAR‐dependent Src modulation of ZDHHC5-EZH2 palmitoylation mechanism

“…Src is commonly expressed in human cancers, including colon, lung, breast, and endometrial tumors [ 19 , 20 ]. Notably, Src is a major component of the processes and pathways that regulate glioblastoma (GBM) tumorigenesis, such as proliferation, invasion, migration, and the epidermal growth factor receptor, Ras/Raf/MEK, and PI3K/AKT pathways [ 2 , 21 ].…”