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Single cell RNA-Seq analysis of A20 tumors derived from tumor-bearing Balb/c mice treated with vehicle or 7.5 mg/kg TAK-981 for 8 h demonstrates induction of IFN1 gene expression in monocytes and T-cells

ABSTRACT: Single cell RNA-Seq analysis of A20 tumors indicated that the IFN1 signature was derived primarily from monocytes and T cells, not the B cell population which includes A20 tumor cells. Single cell RNA-Seq analysis characterized the effect of TAK-981 on B cells (n=4513, includes both A20 B lymphoma tumor cells and WT B cells), erythrocytes (n=238), monocytes (n=85) and T cells (n=107) from A20 tumors responding to treatment with TAK-981. Tumors were harvested 8 h after treatment of A20 tumor-bearing Balb/c mice with either vehicle or 7.5 mg/kg TAK-981 and subjected to scRNA-Seq.

ORGANISM(S): Mus musculus

PROVIDER: GSE173117 | GEO | 2021/04/23

REPOSITORIES: GEO

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Activation of IFN1 signaling by TAK-981 in blood, spleen, or tumor of A20-tumor bearing or B16F10-tumor bearing mice

Project description:Intravenous administration of TAK-981 to Balb/c or C57BL/6 mice bearing A20 or B16F10 syngeneic tumors, respectively, resulted in a strong induction of IFN1 pathway genes in peripheral blood leukocytes, spleen and A20 tumor tissues. TAK- 981 dependent upregulation of IFN1 mRNA signature was determined from RNA-Seq data in peripheral blood, spleen and tumor of BALB/c mice bearing A20 tumors. Upregulation of IFN1 ssGSEA scores were calculated in peripheral blood at 4h (P = 0.0011) and 8h (P = 0.0001), in spleen at 4h (P = 0.0002) and 8h (P = 0.0020), and in tumor at 4h (P = 0.0095) and 8h (P = 0.0033) after treatment with the indicated doses of TAK-981. Dose dependent upregulation of IFN1 mRNA signature by TAK-981 was determined from RNA-Seq data in peripheral blood and spleen of C57BL/6 mice bearing B16F10 tumors. Upregulation of IFN1 ssGSEA scores in the blood at 4h (P = 0.001) and 8h (P = 0.0125) and in the spleen at 4h (P = 0.0019) and 8h (P = 0.0796) after treatment with the indicated concentrations of TAK-981. No upregulation of ssGSEA scores was detected in tumors at 4h (P=0.4295) or 8h (P=0.9706) after treatment with TAK-981. P values were calculated by Welch’s ANOVA test.

2021-04-23 | GSE173114 | GEO

Most cancer cell lines give very modest transcriptional regulation following treatment with the SUMO activating enzyme inhibitors TAK-981 or ML-792

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2021-04-23 | GSE173116 | GEO

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

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2024-04-24 | GSE185841 | GEO

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

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2024-02-28 | GSE255279 | GEO

TAK-981

Project description:TAK-981

| PRJNA723842 | ENA

SUMOylation inhibitor TAK-981 (Subasumstat) synergizes with 5-azacitidine in preclinical models of acute myeloid leukemia

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2023-08-29 | GSE212330 | GEO

Targeting Pancreatic Cancer by TAK-981, a SUMOylation Inhibitor that Activates the Immune System and Blocks Tumor Cell Cycle Progression

Project description:The 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) is lower than 8%. PDAC has the characteristics of high-density stroma and a distinctive immunosuppressive microenvironment and is profoundly resistant to all forms of chemo and immunotherapy. SUMOylation is a reversible post-translational modification required for cell cycle progression. We found that SUMOylation is increased in PDAC patient samples compared to primary pancreatic tissue. TAK-981, a novel highly selective and potent small molecule inhibitor of the SUMO activation enzyme E1 (SAE), selectively decreased SUMOylation in PDAC cells at the nanomolar range, thereby causing a G2/M cell cycle arrest, mitotic failure and chromosomal segregation defects. In vivo TAK-981 efficiently limited the tumor burden in the KPC3 syngeneic mouse model without evidence of general toxicity. Interestingly, we found that TAK-981 modulates the immune system, up-regulating CD8+ T cells, NK cells and down-regulating B cells in peripheral blood, spleen, lymph nodes. Treatment of mouse primary T cells ex vivo with TAK-981 activated STAT1, the key transcription factor induced by interferon signaling. Our findings indicate that inhibition of the SUMO pathway might be a potential clinical strategy to target PDAC by inhibiting tumor cell division and activating anti-tumor immunity.

2022-01-10 | PXD024521 | Pride

Targeting Pancreatic Cancer by TAK-981, a SUMOylation Inhibitor that Activates the Immune System and Blocks Cancer Cell Cycle Progression in a Preclinical Model

Project description:Pancreatic ductal adenocarcinoma (PDAC) has the characteristics of high-density desmoplastic stroma, a distinctive immunosuppressive microenvironment and is profoundly resistant to all forms of chemo and immunotherapy, leading to a 5-year survival rate of 9%. Our study aims to add novel small molecule therapeutics for the treatment of PDAC. We have studied whether TAK-981, a novel highly selective and potent small molecule inhibitor of the SUMO activating enzyme E1 (SAE) could be used to treat a preclinical syngeneic PDAC mouse model. We found that SUMOylation, a reversible post-translational modification required for cell cycle progression, is increased in PDAC patient samples compared to normal pancreatic tissue. TAK-981 decreased SUMOylation in PDAC cells at the nanomolar range, thereby causing a G2/M cell cycle arrest, mitotic failure and chromosomal segregation defects. TAK-981 efficiently limited tumor burden in the KPC3 syngeneic mouse model without evidence of systemic toxicity. In vivo treatment with TAK-981 enhanced the proportions of activated CD8 T cells and NK cells but transiently decreased B cell numbers in peripheral blood, spleen and lymph nodes. ScRNA sequencing revealed activation of the interferon response upon TAK-981 treatment in lymphocytes including T, B and NK cells. TAK-981 treatment of CD8 T cells ex vivo induced activation of STAT1 and interferon target genes. Our findings indicate that pharmacological inhibition of the SUMO pathway represents a potential strategy to target PDAC via a dual mechanism: inhibiting cancer cell cycle progression and activating anti-tumor immunity by inducing interferon signaling.

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Activation of IFN1 signaling by TAK-981 in blood, spleen, or tumor of A20-tumor bearing or B16F10-tumor bearing mice

Project description:Activation of IFN1 signaling by TAK-981 in blood, spleen, or tumor of A20-tumor bearing or B16F10-tumor bearing mice

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Pharmacologic targeting of SUMOylation drives mitochondrial dysfunction and metabolic alterations in B cell Malignancies

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2024-02-02 | GSE254913 | GEO

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