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A bruton’s tyrosine kinase inhibitor reduces stemness and invasiveness of patient-derived glioblastoma tumorspheres

ABSTRACT: Glioblastoma (GBM), the most prevalent primary brain tumor, remains incurable due to the presence of cancer stem cells (CSC), which can be isolated as tumorspheres (TS) that exhibits classical characteristics of CSCs including stemness and invasiveness. The significantly elevated expression of Bruton’s tyrosine kinase (BTK) in GBM tissues identifies BTK as a potential therapeutic target in GBM. Consequently, ibrutinib, an FDA-approved BTK inhibitor for hematological malignancies, has been repurposed as a candidate for GBM treatment, demonstrating inhibitory effects on proliferation, stemness, and invasiveness of GBM cell lines and TSs. However, its broad-spectrum activity targeting other Tec family kinases and members of the epidermal growth factor receptor (EGFR) family, poses potential life-threatening risks, necessitating the development of more selective alternatives. To address this, BTK selective analogs (SPA1758, SPA1763, SPA8004, SPA8007, SPA8009) were synthesized with the aim of targeting two key characteristics of GBM TSs: stemness and invasiveness. WST and ATP assays identified SPA8007 and SPA8009 as the most effective candidates with superior cytotoxic effects in TSs. Additionally, both SPA8007 and SPA8009 significantly inhibited neurosphere formation and reduced invasiveness in GBM TSs. Furthermore, SPA8007 demonstrated improved survival rates in a GBM xenograft mouse model and reduced the expression of invasiveness markers significantly, as observed in immunohistochemistry (IHC) analysis. These findings highlight SPA8007 as potential novel chemotherapeutic agents with high specificity and efficacy to enhance GBM therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288022 | GEO | 2025/04/01

REPOSITORIES: GEO

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Project description:Myeloid-derived suppressor cell (MDSC) levels are elevated in cancer patients and contribute to reduced efficacy of immune checkpoint therapy. MDSC express Bruton’s Tyrosine Kinase (BTK) and BTK inhibition with ibrutinib, an FDA-approved irreversible inhibitor of BTK, leads to reduced MDSC expansion/function in mice and significantly improves the anti-tumor activity of anti-PD-1 antibody treatments. Single-cell RNA sequencing (scRNA-seq) was used to characterize the effect of ibrutinib on gene expression of FACS-enriched MDSC from patients with different cancer types (breast, melanoma, head and neck squamous cell cancer - HNSCC). Melanoma patient MDSC were treated in vitro for 4h with 5 µM ibrutinib or DMSO, processed for scRNA-seq using the Chromium 10x Genomics platform, and analyzed via the Seurat v4 standard integrative workflow. Baseline gene expression of MDSC from breast and HNSCC cancer patients revealed similarities among the top expressed genes. In vitro ibrutinib treatment of MDSC from melanoma patients resulted in significant changes in gene expression. GBP1, IL 1β and CXCL8 were among the top downregulated genes while RGS2 and ABHD5 were among the top upregulated genes (p<0.001). double positive CD14+CD15+ MDSC and PMN-MDSC responded similarly to BTK inhibition and exhibited more pronounced gene changes when compared to early MDSC and M-MDSC. Pathway analysis revealed significantly downregulated pathways including TREM1, nitric oxide signaling, and IL 6 signaling (p<0.004). ScRNA-seq revealed characteristic gene expression patterns for MDSC from different cancer patients. BTK inhibition led to the downregulation of multiple genes and pathways important to MDSC function and migration. Myeloid-derived suppressor cell (MDSC) levels are elevated in cancer patients and contribute to reduced efficacy of immune checkpoint therapy. MDSC express Bruton’s Tyrosine Kinase (BTK) and BTK inhibition with ibrutinib, an FDA-approved irreversible inhibitor of BTK, leads to reduced MDSC expansion/function in mice and significantly improves the anti-tumor activity of anti-PD-1 antibody treatments. Single-cell RNA sequencing (scRNA-seq) was used to characterize the effect of ibrutinib on gene expression of FACS-enriched MDSC from patients with different cancer types (breast, melanoma, head and neck squamous cell cancer - HNSCC). Melanoma patient MDSC were treated in vitro for 4h with 5 µM ibrutinib or DMSO, processed for scRNA-seq using the Chromium 10x Genomics platform, and analyzed via the Seurat v4 standard integrative workflow. Baseline gene expression of MDSC from breast and HNSCC cancer patients revealed similarities among the top expressed genes. In vitro ibrutinib treatment of MDSC from melanoma patients resulted in significant changes in gene expression. GBP1, IL 1β and CXCL8 were among the top downregulated genes while RGS2 and ABHD5 were among the top upregulated genes (p<0.001). double positive CD14+CD15+ MDSC and PMN-MDSC responded similarly to BTK inhibition and exhibited more pronounced gene changes when compared to early MDSC and M-MDSC. Pathway analysis revealed significantly downregulated pathways including TREM1, nitric oxide signaling, and IL 6 signaling (p<0.004). ScRNA-seq revealed characteristic gene expression patterns for MDSC from different cancer patients. BTK inhibition led to the downregulation of multiple genes and pathways important to MDSC function and migration.

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A bruton’s tyrosine kinase inhibitor reduces stemness and invasiveness of patient-derived glioblastoma tumorspheres

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