Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin.
Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin.
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DOI：
10.1016/j.gendis.2023.01.002
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发表时间：
2024-01
期刊：
影响因子：
6.8
通讯作者：
Hou, Yu
中科院分区：
文献类型：
--
作者：
Chen, Zhe;Guo, Qian;Huang, Shichen;Li, Lei;Wu, Feng;Liu, Zhilong;Li, Zhigang;Chen, Tao;Song, Guanbin;Xu, Shuangnian;Chen, Jieping;Hou, Yu
靶向FOXO3A（叉头转录因子）的治疗代表了抑制急性髓性白血病（AML）的一种有前途的策略。然而，缺乏靶向FOXO3A的有效抑制剂，并且适应性反应信号减弱了FOXO3A耗竭对AML细胞的细胞毒性作用。在这里，我们发现FOXO3A缺陷诱导参与mTOR反应性激活的代偿反应，导致信号反弹和适应性抵抗。线粒体代谢作用于mTOR下游，通过活性氧（ROS）引起JNK/c-JUN的活化。在分子水平上，FOXO3A直接与G蛋白γ亚基7（GNG 7）的启动子结合并保持其表达，而GNG 7与mTOR相互作用并限制mTOR的磷酸化激活。因此，F0X03A和mTOR的组合抑制在AML小鼠模型中显示出对AML细胞和AML存活的协同细胞毒性作用。通过基于结构的虚拟筛选，我们报告了一个有效的小分子FOXO 3A抑制剂（Gardenoside），其表现出很强的抗FOXO 3A DNA结合作用。栀子苷与雷帕霉素协同作用，在AML患者来源的异种移植模型中显著降低肿瘤负荷并延长生存期。这些结果表明，mTOR可以介导对FOXO3A抑制的适应性抗性，并验证了用于治疗AML的组合方法。
Therapeutic targeting FOXO3A (a forkhead transcription factor) represents a promising strategy to suppress acute myeloid leukemia (AML). However, the effective inhibitors that target FOXO3A are lacking and the adaptive response signaling weakens the cytotoxic effect of FOXO3A depletion on AML cells. Here, we show that FOXO3A deficiency induces a compensatory response involved in the reactive activation of mTOR that leads to signaling rebound and adaptive resistance. Mitochondrial metabolism acts downstream of mTOR to provoke activation of JNK/c-JUN via reactive oxygen species (ROS). At the molecular level, FOXO3A directly binds to the promoter of G protein gamma subunit 7 (GNG7) and preserves its expression, while GNG7 interacts with mTOR and restricts phosphorylated activation of mTOR. Consequently, combinatorial inhibition of FOXO3A and mTOR show a synergistic cytotoxic effect on AML cells and prolongs survival in a mouse model of AML. Through a structure-based virtual screening, we report one potent small-molecule FOXO3A inhibitor (Gardenoside) that exhibits a strong effect of anti-FOXO3A DNA binding. Gardenoside synergizes with rapamycin to substantially reduce tumor burden and extend survival in AML patient-derived xenograft model. These results demonstrate that mTOR can mediate adaptive resistance to FOXO3A inhibition and validate a combinatorial approach for treating AML.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
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Giefing, Maciej
影响因子：
4.8
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Plas, David R.
影响因子：
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Platanias, Leonidas C.
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