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.

The SUMOylation inhibitor TAK-981 (Subasumstat) triggers IFN-I-dependent activation of Natural Killer cells against Acute Myeloid Leukemias

“…As we demonstrate that TAK-981 can activate AML patient's NK cells, it could be used after CR to increase NK cells activity towards residual AML cells. TAK-981 would thus have a dual anti-leukemic effect by targeting AML cells directly as we and others have recently shown (8,31) and indirectly via the activation of patient's own NK cells. Altogether, this would maximize the chances to control minimal residual disease (MRD), which is largely responsible for the high relapse rate in AML.…”

“…Human AML cell lines U937-LucZsGreen and THP-1-LucZsGreen express both luciferase and ZsGreen protein (8). AML cell lines and human primary cells were cultured with RPMI 1640 (R8758 Sigma-Aldrich) medium complemented with 10% FBS, Penicillin and Streptomycin, at 37°C / 5% CO2.…”

“…We and others have recently shown that TAK-981, a first-in-class inhibitor of the SUMO E1 activating enzyme, has potent antileukemic activity in AML preclinical models (8). In addition to a direct cytotoxic effect on the leukemic cells through the induction of their differentiation and death, inhibition of SUMOylation upregulates NK activating ligands (MICA/MICB and ICAM-1) at the surface of AML cells and favors their killing by NK cells (8). Along the same line, inhibition of the SUMO pathway upregulates Poliovirus Receptor (PVR), at the surface of multiple myeloma cells, favoring their recognition by DNAM1-activating receptor and killing by NK cells (9).…”

“…One major role of SUMOylation is the control of gene expression through the modification of various transcription factors and co-regulators (6,7). We and others have recently shown that TAK-981, a first-in-class inhibitor of the SUMO E1 activating enzyme, has potent antileukemic activity in AML preclinical models (8). In addition to a direct cytotoxic effect on the leukemic cells through the induction of their differentiation and death, inhibition of SUMOylation upregulates NK activating ligands (MICA/MICB and ICAM-1) at the surface of AML cells and favors their killing by NK cells (8).…”

Protein Stability Regulation in Osteosarcoma: The Ubiquitin-like Modifications and Glycosylation as Mediators of Tumor Growth and as Targets for Therapy

“…Indeed, a possible way to achieve SUMOylation inhibition in osteosarcoma could arise from the use of the small molecule TAK-981 (also called Subasumstat), an inhibitor of the SUMO E1 activating enzyme [ 134 ]. As seen in other cancers such as leukemia and lymphomas, TAK-981 administration has resulted in activation of the immune response, possibly leading to cancer regression [ 135 , 136 , 137 ]. However, studies on the use of TAK-981 in osteosarcoma are yet to be performed.…”