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Transcriptome analysis of J558 allograft mouse model treated with the CDC7-specific inhibitor TAK-931 [RNA-seq]

ABSTRACT: To comprehensively evaluate in vivo inflammatory effects of TAK-931 in tumor microenvironment, RNA-seq was conducted in the J558 allograft mouse model. The GSEA revealed significant enrichment of inflammatory hallmarks in TAK-931-treated allografts. Metascape analyses also visualized that the network modules of the inflammatory signaling pathways were predominantly enriched.

ORGANISM(S): Mus musculus

PROVIDER: GSE244988 | GEO | 2023/11/05

REPOSITORIES: GEO

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Gene expression profile at single cell level of J558 allograft mouse model treated with the CDC7-specific inhibitor TAK-931 [scRNA-seq]

Project description:To comprehensively evaluate in vivo inflammatory effects of TAK-931 in tumor microenvironment, scRNA-seq was conducted in the J558 allograft mouse model. The tSNE plots and the expression dot plots showed cellular components in the allografts classified by the indicated TME markers: cancer cell (J558 allograft), monocyte, CD8+ T cell, CD4+ T cell, NK cell, endothelial cell, fibroblast, and undefined, demonstrating that TAK-931 treatment prominently promoted tumor infiltration of both adaptive (CD8+ T cell and CD4+ T cell) and innate (NK cells and monocytes) immune cells in the allografts.

2023-11-05 | GSE244986 | GEO

Transcriptome analysis of HeLa cells treated with the CDC7-specific inhibitor TAK-931 [RNA-seq]

Project description:The results showed that 48-h treatment upregulated 138 genes and 72-h treatment upregulated 504 genes. In the Metascape analyses, the TNF signaling pathway was a dominant network module in the 48-h treatment group, while the inflammatory-related modules were more intensively accumulated, and the signaling networks expanded to the surrounding various modules in the 72-h treatment. Our signaling module results indicate that the TAK-931-induced cellular senescence progressed in a time-dependent manner, and mTOR pathways plays important roles in viability for TAK-931-induced senescent cells.

2023-11-05 | GSE245063 | GEO

Gene expression profile at single cell level of HeLa cells treated with the CDC7-specific inhibitor TAK-931 [scRNA-seq]

Project description:We performed scRNA-seq analyses to determine the transcriptional landscape of the TAK-931-induced aneuploid cells at the single-cell levels. HeLa cells were treated with DMSO or TAK-931 (300 nM) for 72 h. In the t-SNE plots, the DMSO- and TAK-931-treated cells were classified in two distinct clusters. Indicating that the major population of the TAK-931-treated aneuploid HeLa cells was transformed to a cell contexture that was transcriptionally distinct from that of DMSO-treated control cells. The hallmark of an inflammatory response was remarkably enriched in the TAK-931 treatment cluster. In addition, the positive cells of inflammatory cytokine/chemokine-related genes, such as CXCL8, IL1B, TNHSF14 and TNFRSF1B, were significantly accumulated in the TAK-931-treatment cluster.

2023-11-05 | GSE244987 | GEO

A Study to Evaluate the Safety, Tolerability, and Activity of TAK-931 in Participants With Metastatic Pancreatic Cancer, Metastatic Colorectal Cancer, and Other Advanced Solid Tumors

Project description:The purpose of this study is to confirm the safety and tolerability of TAK-931 in a cohort of Western participants with metastatic solid tumors and to evaluate the anti-tumor activity of TAK-931 in participants with metastatic pancreatic cancer, colorectal cancer (CRC), squamous esophageal cancer (sqEC), and squamous non-small-cell lung cancer (sqNSCLC).

| 2252731 | ecrin-mdr-crc

TAK-981

Project description:TAK-981

| PRJNA723842 | ENA

SUMOylation inhibitor TAK-981 potentiates rituximab activity by Type I IFN-dependent macrophage and NK cell stimulation

Project description:SUMOylation is a reversible post-translational modification that has been implicated in the regulation of various cellular processes including inflammatory responses and expression of Type I interferons (IFN1). In this report, we have explored the activity of the selective small molecule SUMOylation inhibitor TAK-981 in promoting antitumor innate immune responses. We demonstrate that treatment with TAK-981 results in IFN1-dependent macrophage and NK cell activation, promoting macrophage phagocytosis and NK cell cytotoxicity in ex vivo assays. Furthermore, pre-treatment with TAK-981 enhanced macrophage phagocytosis or NK cell cytotoxicity against CD20-positive target cells in combination with the anti-CD20 antibody rituximab. In vivo studies demonstrated synergistic antitumor activity of TAK-981 and rituximab in CD20-positive lymphoma xenograft models. TAK-981 is currently being studied in phase 1 clinical trials (NCT03648372, NCT04074330, NCT04776018, and NCT04381650) for the treatment of patients with lymphomas and solid tumors.

2024-04-24 | GSE185841 | GEO

Marchantia polymorpha subsp. ruderalis cultivar:Tak-1 + Tak-2

Project description:Marchantia polymorpha subsp. ruderalis cultivar:Tak-1 + Tak-2 Genome sequencing and assembly

| PRJNA310693 | ENA

A genome-wide CRISPR/Cas9 screen in acute myeloid leukemia cells identifies regulators of TAK-243 sensitivity

Project description:TAK-243 is a first-in-class inhibitor of ubiquitin-like modifier activating enzyme 1 (UBA1) that catalyzes ubiquitin activation, the first step in the ubiquitylation cascade. Based on its preclinical efficacy and tolerability, TAK-243 has been advanced to phase 1 clinical trials in advanced malignancies. Nonetheless, the determinants of TAK-243 sensitivity remain largely unknown. Here, we conducted a genome-wide CRISPR/Cas9 knockout screen in acute myeloid leukemia (AML) cells in the presence of TAK-243 to identify genes essential for TAK-243 action. We identified BEN domain-containing protein 3 (BEND3), a transcriptional repressor and a regulator of chromatin organization, as the top gene whose knockout confers resistance to TAK-243

2021-01-13 | GSE164639 | GEO

Comparative hepatic transcriptome analyses revealed possible pathogenic mechanisms of fasiglifam (TAK-875)-induced acute liver injury in mice

Project description:Fasiglifam (TAK-875), a G protein-coupled receptor 40 (GPR40) agonist, was a drug candidate for type 2 diabetes. However, its development was terminated in phase 3 trials due to liver safety concerns. Although TAK-875 was reported to inhibit hepatobiliary transporters and disturb bile acid disposition, pathogenic mechanisms of TAK-875-induced liver injury are not fully understood. In this study, we sought to identify the mechanisms with a hepatic genome-wide transcriptomic analysis in a murine model. We demonstrated that, among the three GPR40 agonists, TAK-875, AMG-837 and TUG-770, only TAK-875 induced acute liver injury in mice. Transcriptome profiles of TAK-875-exposed liver was compared with those of non-hepatotoxic analogues AMG-837 and TUG-770 as negative controls and those of classical hepatotoxicants concanavalin A and carbon tetrachloride as positive controls. The comparative hepatic transcriptome analyses revealed the enrichment of genes involved in inflammation, endoplasmic reticulum (ER) stress, apoptosis, and hepatic lipid accumulation, suggesting that these events play pathophysiologic roles in the development of TAK-875-induced liver injury. These results were validated by quantitative PCR with significant changes in chemokines, danger signals, ER stress mediators, proapoptotic factors, and hepatic steatosis markers only in TAK-875-exposed liver. Pretreatment of TAK-875-administered mice with an ER stress inhibitor 4-phenylbutyric acid (4-PBA) alleviated the liver injury. Consistent with the in vivo study, pretreatment of HepG2 cells with 4-PBA significantly improved the decrease of cell viability induced by TAK-875. In conclusion, by a comprehensive transcriptomic analysis of GPR40 agonists, we found multiple possible processes that contribute to TAK-875-induced acute liver injury in mice.

2018-10-10 | GSE112140 | GEO

The SUMOylation inhibitor TAK-981 induces a transcriptional reprogramming in human Natural Killer cells [RNA-seq]

Project description:SUMOylation, a post-translational modification of the ubiquitin family plays a critical role in the regulation of proteins function and fate. TAK-981 (Subasumstat) is a first-in-class inhibitor of the SUMO-activating enzyme used in various phase I/II clinical trials for solid tumors and lymphomas. In addition to its direct cytotoxic effect on cancer cells, TAK-981 activates anti-tumor immune response. We show here that TAK-981 activates human natural killer cells. TAK-981 mostly regulates genes involved in inflammation and immune response, in particular those related to the type-I and type-II interferon pathway.

2024-02-28 | GSE255279 | GEO

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