SUMOylation抑制剂TAK-981(亚苏马斯塔)与5-azacitidine在急性髓系白血病的临床前模型中呈协同作用。
SUMOylation inhibitor TAK-981 (subasumstat) synergizes with 5-azacitidine in preclinical models of acute myeloid leukemia.
发表日期:2023 Aug 24
作者:
Ludovic Gabellier, Marion De Toledo, Mehuli Chakraborty, Dana Akl, Rawan Hallal, Mays Aqrouq, Giovanni Buonocore, Clara Recasens-Zorzo, Guillaume Cartron, Abigaïl Delort, Marc Piechaczyk, Denis Tempé, Guillaume Bossis
来源:
HAEMATOLOGICA
摘要:
急性髓系白血病(AML)是一种预后不良的严重血液恶性肿瘤。厚岛甘丁脯基化这种蛋白质翻译后修饰起着白血病发生和AML对治疗反应的关键作用。本文中,我们展示了首例厚岛甘丁脯基化抑制剂TAK-981(亚喹脯酸甲基酯)在各种AML临床前模型中具有强效的抗白血病活性。TAK-981能够选择性靶向AML细胞系和患者原始细胞在体内外以及移植小鼠体内,对正常造血细胞的毒性较小。此外,TAK-981与5-氮杂胞苷(AZA)呈现协同作用,AZA被广泛用于与BCL-2抑制剂维拉托克拉合用以治疗无法接受标准化疗的AML患者。有趣的是,TAK-981+AZA组合在体外和体内的抗白血病活性均高于AZA+维拉托克拉组合,至少在所测试的模型中是如此。从机制上看,TAK-981能够增强AZA诱导的转录重编程,促进白血病细胞的凋亡、细胞周期的变化和分化。此外,TAK-981+AZA和炎症、免疫反应通路相关基因的表达有关。特别地,TAK-981+AZA处理会导致AML细胞释放I型干扰素(IFN-I)。最后,TAK-981+AZA会导致AML细胞表面天然杀伤细胞(NK)活化配体(MICA/B)和粘附蛋白(ICAM-1)的表达增加。一致性地,TAK-981+AZA处理的AML细胞可以激活NK细胞并增加它们的细胞毒活性。因此,利用TAK-981靶向厚岛甘丁脯基化可能是一种既增强AML细胞对AZA的敏感性,又减少它们免疫逃逸能力的有希望的策略。
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.