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Genes & Diseases

Genes & Diseases

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

Published:25 January 2023 DOI: PMID: 37588187
Zhe Chen , Qian Guo , Shichen Huang , Lei Li , Feng Wu , Zhilong Liu , Zhigang Li , Tao Chen , Guanbin Song , Shuangnian Xu , Jieping Chen , Yu Hou

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 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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Procduct Name CAS Molecular Formula Supplier Price
GARDENOSIDE 24512-62-7 C17H24O11 253 suppliers $75.00-$3320.00
GARDENOSIDE 24512-62-7 C17H24O11 253 suppliers $75.00-$3320.00
GARDENOSIDE 24512-62-7 C17H24O11 253 suppliers $75.00-$3320.00
GARDENOSIDE 24512-62-7 C17H24O11 253 suppliers $75.00-$3320.00
Gardenoside 24512-62-7 C17H24O11 - Inquiry
Gardenoside 24512-62-7 C17H24O11 - Inquiry

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