Combination of ATO with FLT3 TKIs eliminates FLT3/ITD+ leukemia cells through reduced expression of FLT3.
Combination of ATO with FLT3 TKIs eliminates FLT3/ITD+ leukemia cells through reduced expression of FLT3.
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DOI：
10.18632/oncotarget.25972
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发表时间：
2018-08-31
期刊：
影响因子：
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通讯作者：
Small D
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文献类型：
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作者：
Nagai K;Hou L;Li L;Nguyen B;Seale T;Shirley C;Ma H;Levis M;Ghiaur G;Duffield A;Small D
携带FLT3/ITD突变的急性髓系白血病（AML）患者预后较差。由于耐药性的产生，选择性 FLT3 酪氨酸激酶抑制剂 (TKI) 单一疗法显示出短暂且有限的疗效。三氧化二砷（ATO、As2O3）已被证明可有效治疗急性早幼粒细胞白血病 (APL)，并且在某些难治性和复发性 AML 及其他血液恶性肿瘤病例中显示出活性。我们探讨了 FLT3 TKI 与 ATO 联合治疗 FLT3/ITD+ 白血病的可行性。 FLT3 TKI 与 ATO 的组合在降低 FLT3/ITD+ 细胞和原代患者样本的增殖、活力和集落形成能力方面表现出协同作用，并增加细胞凋亡。相反，没有观察到针对野生型FLT3白血病细胞的协同作用。 ATO 降低了 FLT3 RNA 及其上游转录调节因子（HOXA9、MEIS1）的表达，并诱导 FLT3 蛋白的多泛素化和降解，部分是通过减少其与 USP10 的结合来实现的。 ATO 还与 FLT3 TKI 协同作用，使 FLT3 自身磷酸化及其下游信号靶标（包括 STAT5、AKT 和 ERK）的磷酸化失活。此外，ATO 与索拉非尼（一种 FLT3 TKI）联合使用，可在体内减少 NSG 受体中 FLT3/ITD+ 白血病细胞的生长。总之，这些结果表明 ATO 是临床试验中与 FLT3 TKI 联合研究的潜在候选药物，以改善 FLT3/ITD+ 白血病的治疗。
Acute myeloid leukemia (AML) patients with FLT3/ITD mutations have a poor prognosis. Monotherapy with selective FLT3 tyrosine kinase inhibitors (TKIs) have shown transient and limited efficacy due to the development of resistance. Arsenic trioxide (ATO, As2O3) has been proven effective in treating acute promyelocytic leukemia (APL) and has shown activity in some cases of refractory and relapsed AML and other hematologic malignances. We explored the feasibility of combining FLT3 TKIs with ATO in the treatment of FLT3/ITD+ leukemias. The combination of FLT3 TKIs with ATO showed synergistic effects in reducing proliferation, viability and colony forming ability, and increased apoptosis in FLT3/ITD+ cells and primary patient samples. In contrast, no cooperativity was observed against wild-type FLT3 leukemia cells. ATO reduced expression of FLT3 RNA and its upstream transcriptional regulators (HOXA9, MEIS1), and induced poly-ubiquitination and degradation of the FLT3 protein, partly through reducing its binding with USP10. ATO also synergizes with FLT3 TKIs to inactivate FLT3 autophosphorylation and phosphorylation of its downstream signaling targets, including STAT5, AKT and ERK. Furthermore, ATO combined with sorafenib, a FLT3 TKI, in vivo reduced growth of FLT3/ITD+ leukemia cells in NSG recipients. In conclusion, these results suggest that ATO is a potential candidate to study in clinical trials in combination with FLT3 TKIs to improve the treatment of FLT3/ITD+ leukemia.