Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin

Zhe Chen; Qian Guo; Shichen Huang; Lei Li; Feng Wu; Zhilong Liu; Zhigang Li; Tao Chen; Guanbin Song; Shuangnian Xu; Jieping Chen; Yu Hou

doi:10.1016/j.gendis.2023.01.002

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Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin

Full Length Articles | 更新时间：2024-02-04

- 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
- Genes & Diseases 2024年1卷第1期页码：397-412
- 作者机构：
  
  1. Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University),Chongqing,China,400038
  2. Institute of Life Sciences, Chongqing Medical University,Chongqing,China,400016
  3. Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University,Chongqing,China,400044
  4. Chongqing Foreign Language School,Chongqing,China,400039
- 作者简介：
- 基金信息：
- DOI：10.1016/j.gendis.2023.01.002
  中图分类号：
- 纸质出版日期：2024，
  
  网络出版日期：2024-1-1，
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Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin[J]. Genes & Diseases, 2024,1(1):397-412.

Zhe Chen, Qian Guo, Shichen Huang, et al. Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin[J]. Genes & Diseases, 2024,1(1):397-412.
Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin[J]. Genes & Diseases, 2024,1(1):397-412. DOI： 10.1016/j.gendis.2023.01.002.

Zhe Chen, Qian Guo, Shichen Huang, et al. Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin[J]. Genes & Diseases, 2024,1(1):397-412. DOI： 10.1016/j.gendis.2023.01.002.

摘要

Abstract

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

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.

关键词

Keywords

AMLCombinatorial inhibitionFOXO3AGNG7mTOR

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