Targeting Pancreatic Cancer by TAK-981, a SUMOylation Inhibitor that Activates the Immune System and Blocks Cancer Cell Cycle Progression in a Preclinical Model
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ABSTRACT:
PROVIDER: PRJNA783638 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR17038703.fastq.gz | Fastqsanger.gz | |||
| SRR17038704.fastq.gz | Fastqsanger.gz |
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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
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.
2022-01-11 | GSE189576 | GEO
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
Project description:Acute Myeloid Leukemias (AML) are severe hematomalignancies with dismal prognosis. The post-translational modification SUMOylation plays key roles in leukemogenesis and AML response to therapies. Here, we show that TAK-981 (subasumstat), a first-in-class SUMOylation inhibitor, is endowed with potent anti-leukemic activity in various preclinical models of AML. TAK-981 targets AML cell lines and patient blast cells in vitro and in vivo in xenografted mice with minimal toxicity on normal hematopoietic cells. Moreover, it synergizes with 5-azacitidine (AZA), a DNA-hypomethylating agent now used in combination with the BCL-2 inhibitor venetoclax to treat AML patients unfit for standard chemotherapies. Interestingly, TAK-981+AZA combination shows higher anti-leukemic activity than AZA+venetoclax combination both in vitro and in vivo, at least in the models tested. Mechanistically, TAK-981 potentiates the transcriptional reprogramming induced by AZA, promoting apoptosis, alteration of the cell cycle and differentiation of the leukemic cells. In addition, TAK-981+AZA treatment induces many genes linked to inflammation and immune response pathways. In particular, this leads to the secretion of type I interferon (IFN-I) by AML cells. Finally, TAK-981+AZA induces the expression of Natural Killer (NK)-activating ligands (MICA/B) and adhesion proteins (ICAM-1) at the surface of AML cells. Consistently, TAK-981+AZA-treated AML cells activate NKs and increase their cytotoxic activity. Targeting SUMOylation with TAK-981 may thus be a promising strategy to both sensitize AML cells to AZA and reduce their immune-escape capacities.
2023-08-29 | GSE212330 | GEO
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
Project description:Modest transcriptional changes has been previously observed in solid tumor cell lines in response to inhibition of SUMOylation by ML-792 and here confirmed with TAK-981, lacking a robust induction of IFN1 genes. Comparable modulation of gene expression in HCT116, MDA-MB-231 and Colo-205 cells by TAK-981 and ML-792. Biological triplicates of HCT116, MDA-MB-231 and Colo-205 cells treated with DMSO, 1 μM ML-792 or 1 μM TAK-981 in vitro for 16 h were analyzed by RNA-Seq. The number of differentially expressed genes (DEGs) with false discovery rate corrected p- values of <0.05 and fold-change values greater than 2 are captured. The degree of gene regulation by TAK-981 is plotted against the degree of gene regulation by ML-792 for the union of their DEGs for each cell line. Data are fitted by linear regression after outliers were removed (7 DEGs from Colo- 205, r^2 = 0.951; 2 DEGs from HCT116, r^2 = 0.836; and 2 DEGs from MDA-MB-231, r^2 = 0.971). Limited and comparable upregulation of human IFN1 mRNA signature in Colo-205, and MDA-MB-231 cells, but not in HCT116 cells, following 16h of treatment with 1uM ML-792 or 1uM TAK-981, as determined by human IFN1 ssGSEA gene signature scores. In vitro treatment of the A20, B16F10, CT26 and MC38 mouse tumor cell lines with TAK-981 did not result in induction of the IFN1 pathway. The overall degree of transcriptional modulation by TAK-981 was relatively modest in the mouse tumor cell lines, with only limited overlap observed in the transcriptional responses to TAK-981, as also observed for the human solid tumor cell lines.
2021-04-23 | GSE173116 | GEO
Project description:Improvement of pancreatic ductal adenocarcinoma (PDAC) patients’ outcomes require exploration of novel therapeutic mechanisms. Thus far, most studies of PDAC therapies, including those inhibiting small ubiquitin-like modifications (SUMOylation), have focused on PDAC epithelial cell biology. The mechanisms by which SUMOylation impacts PDAC in the context of its tumor microenvironment (TME) are poorly understood. We used clinically relevant orthotopic PDAC mouse models to investigate the effect of SUMOylation inhibition using a specific, clinical stage compound, TAK-981. TAK-981 monotherapy improved survival in immunocompetent mice. However, in contrast to its inhibition of PDAC cell proliferation in vitro, the survival benefit of TAK-981 in vivo is dependent on the presence of T cells. Induction of adaptive anti-tumor immunity is the dominant anti-tumor effect of SUMOylation inhibition in vivo. To elucidate the mechanism of adaptive immunity, we performed comparative single cell transcriptomics analyses of murine and human PDAC tumors, including cancer cells, T cells, tumor associated macrophages (TAM) and cancer associated fibroblasts (CAF), in combination with immunofluorescence, immunohistochemistry, western blots and qPCR. Mechanistically, SUMOylation regulates T cell activation and differentiation. In addition, TAK-981 changed gene expression in TAM, CAF and cancer cells that are likely to enhance the anti-tumor T cell response. These findings provide rationale for combination strategies to augment adaptive immune responses to PDAC that are necessary for durable disease control in PDAC patients.
2024-09-02 | GSE212446 | GEO
Project description:Sumoylation is a post-translational modification process that is deregulated in cancer. We foundthat sumoylation machinery was overexpressed in diffuse large B-cell lymphoma (DLBCL).Treatment with TAK-981, a SUMO-activating enzyme (SAE) inhibitor, induced desumoylationof cytoplasmic and mitochondrial proteins, restricting growth of DLBCL and mantle celllymphoma (MCL) cell lines and primary cells. DLBCL cells treated with TAK-981 exhibitedDNA damage, G2 arrest and downregulation of DNA repair, MYC and OxPhos pathways. SAEinhibition disrupted mitochondrial integrity and function, accompanied by mitophagy and rapidaccumulation of ROS. Metabolomic profiling revealed decreases in Krebs cycle substrates, andSeahorse respirometry confirmed dramatic reduction in OxPhos upon SAE inhibition. CRISPR-Cas9 loss-of-function library screens implicated NFκB, TP53, DNA damage andcentromere/telomere gene pathways in resistance to SAE inhibition; knockout of TP53 or BAXrescued DLBCL cells from TAK-981-induced apoptosis. Treatment with TAK-981 prolongedsurvival of mice xenografted with DLBCL and MCL PDX tumors. Thus, sumoylation is apromising target in lymphoid malignancies.
2024-02-02 | GSE254913 | GEO
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