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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE212330 | GEO | 2023/08/29

REPOSITORIES: GEO

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Project description:Mantle cell lymphoma (MCL) is a rare, highly heterogeneous type of B-cell non-Hodgkin’s lymphoma (NHL) driven by multiple genetic mutations disrupting cell cycle regulation and DNA damage response. Despite advances in therapy, novel treatment approaches are needed especially for highly proliferative MCL which has a particularly progressive clinical course even in the era of Bruton’s tyrosine kinase therapy. The sumoylation pathway is known to be upregulated in many cancers including lymphoid malignancies. However, little is currently known about the role of the sumoylation pathway and its oncogenic potential in MCL. We found extensive upregulation of the sumoylation pathway in MCL, particularly at the level of the E1 enzymes SAE1 and SAE2, with elevated expression levels of sumoylation enzyme components showing a worse prognosis and a strong positive correlation with cell cycle associated genes. Targeting the sumoylation pathway with TAK-981, a first in class sumoylation inhibitor currently being investigated in a clinical study of B-cell NHL in combination with rituximab (NCT04074330), resulted in potent loss of sumoylation in MCL cells with significant activity in in-vitro and in vivo models of MCL, including ibrutinib resistance cases. We found mitotic dysregulation to be an important, although not all encompassing mechanism of cell death upon loss of sumoylation of TAK-981 in MCL cells. We uncovered a diverse sumoylation program upon mitosis entry that was significantly reduced with TAK-981. Centromeric localization of the well known sumoylation substrate topoisomeraseIIA (TopIIA) was significantly abrogated upon mitosis entry, likely contributing at least in part to the mitotic dysregulation seen in MCL cells. This mechanism is highly relevant as TopIIA is significantly upregulated in MCL with SAE1/2 overexpression. Our study, in addition to the recently described immunomodulatory activity of TAK-981, not only validates SAE1/2 as a therapeutic target in MCL but also opens the door to further mechanistic work to uncover how to best use desumoylation therapy to treat MCL and other lymphoid malignancies.

Project description:Background:Aberrant DNA methylation that silences tumor suppressor genes occurs frequently in patients with acute myeloid leukemia (AML). Treatment of AML patients with the inhibitor of DNA methylation, 5-aza-2'-deoxycytidine (5-AZA-CdR) can induce complete remissions, but most patients will relapse. The clinical efficacy of 5-AZA-CdR may be influenced by its limited capacity to activate tumor suppressor genes silenced by methylation of lysine 27 histone H3 (H3K27) by EZH2. In order to overcome this limitation, we investigated previously the antileukemic action of 5-AZA-CdR in combination with the EZH2 inhibitor, 3-deazaneplanocin A (DZNep) on HL-60 AML cells. We observed a remarkable synergistic interaction against these AML cells for this combination. In this study, we investigated in more depth the action of 5-AZA-CdR plus DZNep on gene expression in AML cells using RNA sequence analysis Result:In a colony assay, 5-AZA-CdR in combination with DZNep exhibited also a potent synergy against another human AML cell line: AML-3. The induction of apoptosis in HL-60 and AML3 leukemic cells by 5-AZA-CdR plus DZNep was also synergistic. RNA sequence analysis on HL-60 leukemic cells showed that the combination of 5-AZA-CdR plus DZNep increased the expression of thousands of genes. The genes upregulated by this combination included genes related to differentiation, development, senescence, apoptosis, and tumor suppressor function. Many of the genes activated by 5-AZA-CdR plus DZNep have the potential to suppress leukemogenesis. Conclusion: The activation of many genes by the combination of 5-AZA-CdR plus DZNep correlates with its synergistic antileukemic action. The block in differentiation is one of the hallmarks of AML.The activation of many genes that program differentiation and development by this combination of epigenetic agents has the potential to reverse this block. The reversal of these two epigenetic genesilencing mechanisms by 5-AZA-CdR plus DZNep merits clinical investigation in patients with AML

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

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