Acute myeloid leukemia (AML) with Fms-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is notoriously hard to treat. We identified two drugs that together form an effective combination therapy against FLT3-ITD AML. One of the drugs, Sorafenib, an inhibitor of FLT3-ITD and other kinase activity, produces an impressive but short-lived remission in FLT3-ITD AML patients. The second, arsenic trioxide (ATO), at therapeutically achievable concentrations, reduces the level of FLT3-ITD and Mcl-1 proteins, and induces apoptosis in leukemic cell lines and in primary cells expressing FLT3-ITD. We linked this relative sensitivity to ATO to low levels of reduced glutathione. While producing proapoptotic effects, ATO treatment also has an unwanted effect whereby it causes the accumulation of the phosphorylated (inactive) form of glycogen synthase kinase 3β (GSK3β), a kinase necessary for apoptosis. When ATO is combined with Sorafenib, GSK3β is activated, Mcl-1 is further reduced, and proapoptotic proteins Bak and Bax are activated. Mice xenografted with FLT3-ITD MOLM13 cell line treated with the Sorafenib/ATO combination have significantly improved survival. This combination has potential to improve the therapeutic outcome of FLT3-ITD–targeted therapy of AML patients. Mol Cancer Ther; 17(9); 1871–80. ©2018 AACR.

中文翻译：

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三氧化二砷和索拉非尼诱导 FLT3-ITD 急性髓系白血病细胞的合成致死

众所周知，具有 Fms 相关酪氨酸激酶 3 内部串联重复 (FLT3-ITD) 突变的急性髓性白血病 (AML) 难以治疗。我们确定了两种药物，它们共同形成了针对 FLT3-ITD AML 的有效联合疗法。其中一种药物索拉非尼是 FLT3-ITD 和其他激酶活性的抑制剂，可在 FLT3-ITD AML 患者中产生令人印象深刻但短暂的缓解。第二种，三氧化二砷 (ATO)，在治疗可达到的浓度下，降低 FLT3-ITD 和 Mcl-1 蛋白的水平，并诱导白血病细胞系和表达 FLT3-ITD 的原代细胞凋亡。我们将这种对 ATO 的相对敏感性与低水平的还原型谷胱甘肽联系起来。在产生促凋亡作用的同时，ATO 治疗也有不利影响，它会导致磷酸化（无活性）形式的糖原合酶激酶 3β (GSK3β) 积累，这是一种细胞凋亡所必需的激酶。当ATO与索拉非尼联合使用时，GSK3β被激活，Mcl-1进一步减少，促凋亡蛋白Bak和Bax被激活。用索拉非尼/ATO 组合处理的 FLT3-ITD MOLM13 细胞系异种移植小鼠的存活率显着提高。这种组合有可能改善 AML 患者的 FLT3-ITD 靶向治疗的治疗结果。摩尔癌症治疗; 17(9); 1871-80 年。©2018 AACR。用索拉非尼/ATO 组合处理的 FLT3-ITD MOLM13 细胞系异种移植小鼠的存活率显着提高。这种组合有可能改善 AML 患者的 FLT3-ITD 靶向治疗的治疗结果。摩尔癌症治疗; 17(9); 1871-80 年。©2018 AACR。用索拉非尼/ATO 组合处理的 FLT3-ITD MOLM13 细胞系异种移植小鼠的存活率显着提高。这种组合有可能改善 AML 患者的 FLT3-ITD 靶向治疗的治疗结果。摩尔癌症治疗; 17(9); 1871-80 年。©2018 AACR。