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Investigation of the anti-tumor mechanism of tirabrutinib, a highly selective Bruton’s tyrosine kinase inhibitor, by transcriptomics

ABSTRACT: Investigation of the anti-tumor mechanism of tirabrutinib, a highly selective Bruton’s tyrosine kinase inhibitor, by transcriptomics

PROVIDER: PRJNA865027 | ENA |

REPOSITORIES: ENA

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Investigation of the anti-tumor mechanism of tirabrutinib, a highly selective Bruton’s tyrosine kinase inhibitor, by transcriptomics

Project description:Tirabrutinib is a highly selective BTK inhibitor for treating hematological malignancies. This study analyzed the anti-tumor mechanism of tirabrutinib with microarray analysis of ABC-DLBCL xenograft model tumors. The comprehensive gene expression analysis revealed that tirabrutinib downregulated IRF-4, MYC, and mTORC1 pathway-related genes in TMD8, suggesting the crucial roles of these pathways in ABC-DLBCL.

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Fenebrutinib, a Bruton’s tyrosine kinase inhibitor, blocks distinct human microglial signaling pathways

Project description:Bruton’s tyrosine kinase (BTK) is an intracellular signaling enzyme that regulates B cell and myeloid cell functions. Due to its involvement in both innate and adaptive immune compartments, inhibitors of BTK have emerged as a therapeutic option in autoimmune disorders such as multiple sclerosis (MS). Brain penetrant small molecule BTK inhibitors may also help to address compartmentalized neuroinflammation which is proposed to underlie MS disease progression. BTK is expressed by microglia, the resident innate immune cells of the brain, however the precise roles of microglial BTK and the impact of BTK inhibitors on microglial functions is still being elucidated. Much research to date has also focused on the effects of BTK inhibitors using rodent disease models. Here we characterize the pharmacological and functional properties of fenebrutinib (FEN), a potent, highly selective, noncovalent, reversible BTK inhibitor, in human microglia and complex human brain cell systems including brain organoids. We find that FEN blocks the effects of microglial FcγR activation including cytokine and chemokine release, microglial clustering and neurite damage in diverse human brain cell systems. Gene expression analyses identified pathways linked to inflammation, matrix metalloproteinase production and cholesterol metabolism that were modulated by FEN treatment. In contrast, FEN had no significant impact on human microglial pathways linked to TLR4 or NLRP3 signaling nor myelin phagocytosis. Our study increases the understanding of BTK functions in human microglial signaling relevant to MS pathogenesis and suggests that FEN could attenuate detrimental microglial activity associated with FcγR activation in MS patients.

2024-10-28 | GSE276803 | GEO

Fenebrutinib, a Bruton’s tyrosine kinase inhibitor, blocks distinct human microglial signaling pathways

Project description:Fenebrutinib, a Bruton’s tyrosine kinase inhibitor, blocks distinct human microglial signaling pathways

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Bruton’s tyrosine kinase (BTK) and indoleamine 2,3-dioxygenase (IDO) block differentiation of inflammatory dendritic cells in tumors [scRNA-seq]

Project description:Dendritic cells (DCs) are pivotal drivers of anti-tumor immunity, but many of the DCs in tumors appear dysfunctional or immunosuppressive. Using mouse models, we found that robustly immunogenic DCs can arise by differentiation from immature myeloid precursor cells during inflammation. In tumors, however, differentiation of these inflammatory DCs was blocked by a cell-intrinsic signaling pathway created by Bruton’s Tyrosine Kinase (BTK) and the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO).

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Bruton’s tyrosine kinase (BTK) and indoleamine 2,3-dioxygenase (IDO) block differentiation of inflammatory dendritic cells in tumors [ATAC-seq]

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Bruton’s Tyrosine Kinase Degradation as a Therapeutic Strategy for Cancer

Project description:The covalent Bruton’s Tyrosine Kinase (BTK) inhibitor ibrutinib is highly efficacious against multiple B-cell malignancies. However, it also has off-target effects and multiple mechanisms of resistance, including the C481S mutation. We hypothesized that small molecule-induced BTK degradation might be able to overcome some of the limitations of traditional enzymatic inhibitors. Here, we demonstrate that BTK degradation results in more durable suppression of signaling and proliferation in cancer cells than BTK inhibition and that BTK degraders are able to efficiently degrade BTK C481S. Moreover, we generated DD-03-171, an optimized lead compound that exhibits enhanced anti-proliferative effects on mantle cell lymphoma (MCL) cells in vitro as well as efficacy in a patient-derived xenograft model of MCL. These data suggest that targeted BTK degradation is an effective therapeutic approach in treating MCL and overcoming ibrutinib resistance, thereby addressing a major unmet need in the treatment of MCL and other B-cell lymphomas.

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Bruton’s tyrosine kinase (BTK) and indoleamine 2,3-dioxygenase (IDO) block differentiation of inflammatory dendritic cells in tumors [Bulk RNA-seq]

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Bruton’s tyrosine kinase inhibitor leads to bidirectional transcript regulation of Nurr1: A new key to Parkinson’s disease

Project description:Parkinson’s disease (PD) is a progressive neurological movement diseases with few therapeutic targets identified to date. The primary treatment for PD is levodopa, but it is only effective in the initial stage and induces side effects of the disease. To address this problem, we unveil the hitherto uncharacterized crucial role of Bruton’s tyrosine kinase protein (BTK) as a bidirectional transcriptional bio-regulator of tyrosine hydroxylase (TH) expression via the modulation of nuclear receptor-related transcription factor 1 (Nurr1). The proteomics competition binding assay revealed that BTK binds to Nurr1 and transactivates TH promoter activity via Nurr1. The BTK inhibitor demonstrated remarkable effects in the mitochondrial permeability transition pore-induced oxidative stress model by significantly attenuating the levels of proinflammatory mediators via WNT/β-catenin and MAPK kinase signaling. These findings highlight the potential efficacy of BTK inhibitors as innovative therapeutics for PD.

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Time resolved quantitative phospho-tyrosine analysis reveals Bruton’s Tyrosine kinase mediated signaling downstream of the mutated granulocyte-colony stimulating factor receptors

Project description:Granulocyte-colony stimulating factor receptor (G-CSFR) controls myeloid progenitor proliferation and differentiation to neutrophils. Mutations in CSF3R (encoding G-CSFR) have been reported in patients with chronic neutrophilic leukemia (CNL) and acute myeloid leukemia (AML); however, despite years of research, the malignant downstream signaling of the mutated G-CSFRs is not well understood. Here, we utilized a quantitative phospho-tyrosine analysis to generate a comprehensive signaling map of G-CSF induced tyrosine phosphorylation in the normal versus mutated (proximal: T618I and truncated: Q741x) G-CSFRs. Unbiased clustering and kinase enrichment analysis identified rapid induction of phospho-proteins associated with endocytosis by the wild-type G-CSFR only; while G-CSFR mutants showed abnormal kinetics of canonical STAT3, STAT5 and MAPK phosphorylation, and aberrant activation of Bruton’s Tyrosine Kinase (Btk). Mutant-G-CSFR-expressing cells displayed enhanced sensitivity (5-fold lower IC50) for Ibrutinib-based chemical inhibition of Btk. Finally, primary murine progenitor cells from G-CSFR-d715x knock-in mice validate activation of Btk by the mutant receptor, and display enhanced sensitivity to Ibrutinib. Together, these data demonstrate the strength of unsupervised proteomics analyses in dissecting oncogenic pathways, and suggest repositioning Ibrutinib for therapy of myeloid leukemia bearing CSF3R mutations.

2018-07-11 | PXD009662 | Pride

Bruton’s tyrosine kinase (BTK) and indoleamine 2,3-dioxygenase (IDO) block differentiation of inflammatory dendritic cells in tumors

Project description:Bruton’s tyrosine kinase (BTK) and indoleamine 2,3-dioxygenase (IDO) block differentiation of inflammatory dendritic cells in tumors

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