Small-molecule SUMO inhibition for biomarker-informed B-cell lymphoma therapy

Abstract

Aberrant activity of the SUMOylation pathway has been associated with MYC overexpression and poor prognosis in aggressive B-cell lymphoma (BCL) and other malignancies. Recently developed small molecule inhibitors of SUMOylation (SUMOi) target the heterodimeric E1 SUMO activation complex (SAE1/UBA2). Here, we report that activated MYC signaling is an actionable molecular vulnerability in vitro and in a pre-clinical murine in vivo model of MYCdriven BCL. While SUMOi conferred direct effects on MYC-driven lymphoma cells, SUMO inhibition also resulted in substantial remodeling of various subsets of the innate and specific immunity in vivo. Specifically, SUMOi increased the number of memory B-cells as well as cytotoxic and memory T-cells, subsets that are attributed a key role within a coordinated antitumor immune response. In summary, our data constitute pharmacologic SUMOi as a powerful therapy in a subset of B-cell lymphomas causing massive remodeling of the normal B-cell and T-cell compartment.

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

“…Hence, the molecular mechanisms underlying the strong and rapid induction of IFNB by TAK-981 remain to be identified. TAK-981-induced IFN-I response was suggested to play a critical role in its anti-tumoral activity through its ability to activate both innate and adaptative anti-tumoral immune responses (10)(11)(12)(13)29). Accordingly, TAK-981 was found to enhance the antitumoral activity of monoclonal antibodies as seen for rituximab (anti-CD20) or daratumumab (anti CD38) in preclinical mouse models of lymphoma and myeloma respectively (11).…”

“…In addition to the overexpression of innate immunity activating ligands by cancer cells, recent studies have reported that inhibition of SUMOylation with TAK-981 activates an anti-tumor immune response and improves the efficiency of immune therapies by directly affecting immune cells. In models of pancreatic cancer and lymphomas, TAK-981 activates CD8 T-cells, NK cells, monocytes and dendritic cells (10)(11)(12)(13), and decreases regulatory T-cells (T-reg) differentiation (14). The immuno-modulatory function of TAK-981 was suggested to rely on its ability to induce type-I Interferon (IFN-I) secretion.…”

Actionable loss of SLF2 drives B‐cell lymphomagenesis and impairs the DNA damage response

“…Of note, the highly effective SUMOi subasumstat/TAK‐981 is currently undergoing early clinical phase testing in lymphoma and further cancer entities. Several studies have already shown the successful application of SUMOi in a variety of cancers, such as pancreatic cancer and BCL (Hoellein et al , 2014 ; Biederstadt et al , 2020 ) and that subasumstat can act via activation of the immune system (Lightcap et al , 2021 ; Demel et al , 2022 ; Kumar et al , 2022 ) or direct killing of tumor cells (Biederstadt et al , 2020 ; Demel et al , 2023 ). Importantly, we here report SLF2 loss as an actionable biomarker for BCL patients.…”

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

“…20,21 Indeed, TAK-981 activates dendritic cells, cytotoxic CD8 + T cells, memory B cells, natural killer (NK) cells and macrophages. [20][21][22][23][24] Moreover, TAK-981 increases antigen presentation by cancer cells, further enhancing anti-tumor immune response. 22 In addition to these effects on the immune micro-environment, TAK-981 can directly induce cancer cells death.…”