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

作者全名："Chen, Zhe; Guo, Qian; Huang, Shichen; Li, Lei; Wu, Feng; Liu, Zhilong; Li, Zhigang; Chen, Tao; Song, Guanbin; Xu, Shuangnian; Chen, Jieping; Hou, Yu"

作者地址："[Chen, Zhe; Li, Lei; Liu, Zhilong; Chen, Tao; Xu, Shuangnian; Chen, Jieping] Army Med Univ, Mil Med Univ 3, Southwest Hosp, Dept Hematol, Chongqing 400038, Peoples R China; [Chen, Zhe; Wu, Feng; Li, Zhigang; Hou, Yu] Chongqing Med Univ, Inst Life Sci, Chongqing 400016, Peoples R China; [Guo, Qian; Song, Guanbin] Chongqing Univ, Coll Bioengn, Key Lab Biorheol Sci & Technol, Minist Educ, Chongqing 400044, Peoples R China; [Huang, Shichen] Chongqing Foreign Language Sch, Chongqing 400039, Peoples R China"

通信作者："Xu, SN; Chen, JP (通讯作者)，Army Med Univ, Mil Med Univ 3, Southwest Hosp, Dept Hematol, Chongqing 400038, Peoples R China.; Hou, Y (通讯作者)，Chongqing Med Univ, Inst Life Sci, Chongqing 400016, Peoples R China."

来源：GENES & DISEASES

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001052633700001

JCR分区：Q1

影响因子：6.8

年份：2024

卷号：11

期号：1

开始页：397

结束页：412

文献类型：Article

关键词：AML; Combinatorial inhibition; FOXO3A; GNG7; mTOR

摘要："Therapeutic targeting FOXO3A (a forkhead transcription factor) represents a prom-ising 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 compensa-tory response involved in the reactive activation of mTOR that leads to signaling rebound and adaptive resistance. Mitochondrial metabolism acts downstream of mTOR to provoke activa-tion 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 re-sults demonstrate that mTOR can mediate adaptive resistance to FOXO3A inhibition and vali-date a combinatorial approach for treating AML.@ 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/)."

基金机构："Chongqing Science Fund for Distinguished Young Scholars, China [81970100]; National Science Foundation of China [82170115, 81700135, CSTB2022BSXM-JCX0005]; Doctor Research Project of Chongqing, China; [CSTB2022NSCQ-JQX0032]"

基金资助正文："This work was supported by the Chongqing Science Fund for Distinguished Young Scholars, China (CSTB2022NSCQ-JQX0032) , National Science Foundation of China (No. 81970100, 82170115 and 81700135) , and the Doctor Research Project of Chongqing, China (No. CSTB2022BSXM-JCX0005) ."