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 article | 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
- Genes & Diseases Vol. 1, Issue 1, Pages: 397-412(2024)
- 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
  CLC：
- Published：2024，
  
  Published Online：1 January 2024，
扫描看全文
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 1(1):397-412(2024)
DOI：

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 1(1):397-412(2024) 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

references

1 E. Papaemmanuil, M. Gerstung, L. Bullinger, et al.Genomic classification and prognosis in acute myeloid leukemia N Engl J Med, 374 (23) (2016), pp. 2209-2221

2 M. Yamashita, P.V. Dellorusso, O.C. Olson, et al.Dysregulated haematopoietic stem cell behaviour in myeloid leukaemogenesis Nat Rev Cancer, 20 (7) (2020), pp. 365-382

3 R.L. Bowman, L. Busque, R.L. LevineClonal hematopoiesis and evolution to hematopoietic malignancies Cell Stem Cell, 22 (2) (2018), pp. 157-170

4 J.L. Carter, K. Hege, J. Yang, et al.Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy Signal Transduct Targeted Ther, 5 (1) (2020), p. 288

5 M.L. Golson, K.H. KaestnerFox transcription factors: from development to disease Development, 143 (24) (2016), pp. 4558-4570

6 S. Hannenhalli, K.H. KaestnerThe evolution of Fox genes and their role in development and disease Nat Rev Genet, 10 (4) (2009), pp. 233-240

7 Y. Liu, X. Ao, W. Ding, et al.Critical role of FOXO3a in carcinogenesis Mol Cancer, 17 (1) (2018), p. 104

8 M.R. Warr, M. Binnewies, J. Flach, et al.FOXO3A directs a protective autophagy program in haematopoietic stem cells Nature, 494 (7437) (2013), pp. 323-327

9 S.M. Sykes, S.W. Lane, L. Bullinger, et al.AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias Cell, 146 (5) (2011), pp. 697-708

10 C.M. Santamaría, M.C. Chillón, R. García-Sanz, et al.High FOXO3a expression is associated with a poorer prognosis in AML with normal cytogenetics Leuk Res, 33 (12) (2009), pp. 1706-1709

11 S.M. Kornblau, N. Singh, Y. Qiu, et al.Highly phosphorylated FOXO3A is an adverse prognostic factor in acute myeloid leukemia Clin Cancer Res, 16 (6) (2010), pp. 1865-1874

12 M.A. Santos, R.B. Faryabi, A.V. Ergen, et al.DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier Nature, 514 (7520) (2014), pp. 107-111

13 P. Jaaks, E.A. Coker, D.J. Vis, et al.Effective drug combinations in breast, colon and pancreatic cancer cells Nature, 603 (7899) (2022), pp. 166-173

14 K. Bertram, P.J. Leary, C. Boudesco, et al.Inhibitors of Bcl-2 and Bruton's tyrosine kinase synergize to abrogate diffuse large B-cell lymphoma growth in vitro and in orthotopic xenotransplantation models Leukemia, 36 (4) (2022), pp. 1035-1047

15 W.H. Wilson, G.W. Wright, D.W. Huang, et al.Effect of ibrutinib with R-CHOP chemotherapy in genetic subtypes of DLBCL Cancer Cell, 39 (12) (2021), pp. 1643-1653

16 Y. He, L. Sun, Y. Xu, et al.Combined inhibition of PI3Kδ and FLT3 signaling exerts synergistic antitumor activity and overcomes acquired drug resistance in FLT3-activated acute myeloid leukemia Cancer Lett, 420 (2018), pp. 49-59

17 J.K. Bruner, H.S. Ma, L. Li, et al.Adaptation to TKI treatment reactivates ERK signaling in tyrosine kinase-driven leukemias and other malignancies Cancer Res, 77 (20) (2017), pp. 5554-5563

18 X. Jiang, P.Y. Mak, H. Mu, et al.Disruption of Wnt/β-catenin exerts antileukemia activity and synergizes with FLT3 inhibition in FLT3-mutant acute myeloid leukemia Clin Cancer Res, 24 (10) (2018), pp. 2417-2429

19 J. Wang, Y. Li, P. Wang, et al.Leukemogenic chromatin alterations promote AML leukemia stem cells via a KDM4C-ALKBH5-AXL signaling axis Cell Stem Cell, 27 (1) (2020), pp. 81-97.e8

20 Z. Chen, L. Li, W. Wu, et al.Exercise protects proliferative muscle satellite cells against exhaustion via the Igfbp7-Akt-mTOR axis Theranostics, 10 (14) (2020), pp. 6448-6466

21 Z. Chen, D. Huo, L. Li, et al.Nuclear DEK preserves hematopoietic stem cells potential via NCoR1/HDAC3-Akt1/2-mTOR axis J Exp Med, 218 (5) (2021), Article e20201974

22 J.B. Baell, G.A. HollowayNew substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays J Med Chem, 53 (7) (2010), pp. 2719-2740

23 R.A. Friesner, J.L. Banks, R.B. Murphy, et al.Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy J Med Chem, 47 (7) (2004), pp. 1739-1749

24 P. van Galen, V. Hovestadt, M.H. Wadsworth II, et al.Single-cell RNA-seq reveals AML hierarchies relevant to disease progression and immunity Cell, 176 (6) (2019), pp. 1265-1281

25 D. Li, T. Li, Z. Shang, et al.Combined inhibition of Notch and FLT3 produces synergistic cytotoxic effects in FLT3/ITD+ acute myeloid leukemia Signal Transduct Targeted Ther, 5 (1) (2020), p. 21

26 Y. Wang, W. Jin, X. Jia, et al.Transcriptional repression of CDKN2D by PML/RARα contributes to the altered proliferation and differentiation block of acute promyelocytic leukemia cells Cell Death Dis, 5 (10) (2014), Article e1431

27 J. Bertacchini, N. Heidari, L. Mediani, et al.Targeting PI3K/AKT/mTOR network for treatment of leukemia Cell Mol Life Sci, 72 (12) (2015), pp. 2337-2347

28 E.M. Beauchamp, S.M. Abedin, S.G. Radecki, et al.Identification and targeting of novel CDK9 complexes in acute myeloid leukemia Blood, 133 (11) (2019), pp. 1171-1185

29 X. Lin, Q. Fang, S. Chen, et al.Heme oxygenase-1 suppresses the apoptosis of acute myeloid leukemia cells via the JNK/c-JUN signaling pathway Leuk Res, 39 (5) (2015), pp. 544-552

30 D. Zhang, Q. Zhou, D. Huang, et al.ROS/JNK/c-Jun axis is involved in oridonin-induced caspase-dependent apoptosis in human colorectal cancer cells Biochem Biophys Res Commun, 513 (3) (2019), pp. 594-601

31 J.R. Wu, R.I. You, C.T. Hu, et al.Hydrogen peroxide inducible clone-5 sustains NADPH oxidase-dependent reactive oxygen species-c-Jun N-terminal kinase signaling in hepatocellular carcinoma Oncogenesis, 8 (8) (2019), p. 40

32 O.H. Yilmaz, R. Valdez, B.K. Theisen, et al.Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells Nature, 441 (7092) (2006), pp. 475-482

33 B.L. Bennett, D.T. Sasaki, B.W. Murray, et al.SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase Proc Natl Acad Sci U S A, 98 (24) (2001), pp. 13681-13686

34 S. Khatri, H. Yepiskoposyan, C.A. Gallo, et al.FOXO3a regulates glycolysis via transcriptional control of tumor suppressor TSC1 J Biol Chem, 285 (21) (2010), pp. 15960-15965

35 C.C. Chen, S.M. Jeon, P.T. Bhaskar, et al.FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and Rictor Dev Cell, 18 (4) (2010), pp. 592-604

36 C.H. Melick, J.L. JewellRegulation of mTORC1 by upstream stimuli Genes, 11 (9) (2020), p. 989

37 S. Hartmann, M. Szaumkessel, I. Salaverria, et al.Loss of protein expression and recurrent DNA hypermethylation of the GNG7 gene in squamous cell carcinoma of the head and neck J Appl Genet, 53 (2) (2012), pp. 167-174

38 K. Shibata, S. Tanaka, T. Shiraishi, et al.G-protein gamma 7 is down-regulated in cancers and associated with p 27kip1-induced growth arrest Cancer Res, 59 (5) (1999), pp. 1096-1101

39 N.M. Duc, H.R. Kim, K.Y. ChungStructural mechanism of G protein activation by G protein-coupled receptor Eur J Pharmacol, 763 (Pt B) (2015), pp. 214-222

40 V. Syrovatkina, K.O. Alegre, R. Dey, et al.Regulation, signaling, and physiological functions of G-proteins J Mol Biol, 428 (19) (2016), pp. 3850-3868

41 J. Liu, X. Ji, Z. Li, et al.G protein γ subunit 7 induces autophagy and inhibits cell division Oncotarget, 7 (17) (2016), pp. 24832-24847

42 W.S. Lai, Y.L. DingGNG7 silencing promotes the proliferation and differentiation of placental cytotrophoblasts in preeclampsia rats through activation of the mTOR signaling pathway Int J Mol Med, 43 (5) (2019), pp. 1939-1950

43 W. Lai, L. YuElevated microRNA 183 impairs trophoblast migration and invasiveness by downregulating FOXP1 expression and elevating GNG7 expression during preeclampsia Mol Cell Biol, 41 (1) (2020) e00236-20

44 D. Obrist, A. Nienhaus, E. Zamaro, et al.Determinants for a successful Sémont maneuver: an In vitro study with a semicircular canal model Front Neurol, 7 (2016), p. 150

45 K.L. Tsai, Y.J. Sun, C.Y. Huang, et al.Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification Nucleic Acids Res, 35 (20) (2007), pp. 6984-6994

46 H. Liang, L. Zhang, H. Wang, et al.Inhibitory effect of gardenoside on free fatty acid-induced steatosis in HepG2 hepatocytes Int J Mol Sci, 16 (11) (2015), pp. 27749-27756

47 E.V. Verovskaya, P.V. Dellorusso, E. PasseguéLosing sense of self and surroundings: hematopoietic stem cell aging and leukemic transformation Trends Mol Med, 25 (6) (2019), pp. 494-515

48 X. Han, Y. Kuang, H. Chen, et al.p19INK4d: More than just a cyclin-dependent kinase inhibitor Curr Drug Targets, 21 (1) (2020), pp. 96-102

49 Y.J. Dai, Y.Y. Wang, J.Y. Huang, et al.Conditional knockin of Dnmt3a R878H initiates acute myeloid leukemia with mTOR pathway involvement Proc Natl Acad Sci U S A, 114 (20) (2017), pp. 5237-5242

50 Z. Ge, C. Song, Y. Ding, et al.Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia Leukemia, 35 (5) (2021), pp. 1267-1278

51 E.R. Lechman, B. Gentner, S.W.K. Ng, et al.miR-126 regulates distinct self-renewal outcomes in normal and malignant hematopoietic stem cells Cancer Cell, 29 (2) (2016), pp. 214-228

52 T. Hoshii, Y. Tadokoro, K. Naka, et al.mTORC1 is essential for leukemia propagation but not stem cell self-renewal J Clin Invest, 122 (6) (2012), pp. 2114-2129

53 Z. Fu, D.J. TindallFOXOs, cancer and regulation of apoptosis Oncogene, 27 (16) (2008), pp. 2312-2319

54 Y. Fang, Y. Yang, C. Hua, et al.Rictor has a pivotal role in maintaining quiescence as well as stemness of leukemia stem cells in MLL-driven leukemia Leukemia, 31 (2) (2017), pp. 414-422

55 E. Manchado, S. Weissmueller, J.P. Morris 4th, et al.A combinatorial strategy for treating KRAS-mutant lung cancer Nature, 534 (7609) (2016), pp. 647-651

56 J. Theruvath, M. Menard, B.A.H. Smith, et al.Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication Nat Med, 28 (2) (2022), pp. 333-344

57 S. Zhang, L. Zhou, B. Hong, et al.Small-molecule NSC59984 restores p53 pathway signaling and antitumor effects against colorectal cancer via p73 activation and degradation of mutant p53 Cancer Res, 75 (18) (2015), pp. 3842-3852

58 Y. Chen, J. Wang, Y. Wang, et al.A propolis-derived small molecule ameliorates metabolic syndrome in obese mice by targeting the CREB/CRTC2 transcriptional complex Nat Commun, 13 (1) (2022), p. 246

59 Y. Sheng, C. Yu, Y. Liu, et al.FOXM1 regulates leukemia stem cell quiescence and survival in MLL-rearranged AML Nat Commun, 11 (1) (2020), p. 928

60 T. Shen, T. Lei, L. Chen, et al.Gardenoside hinders caspase-1-mediated hepatocyte pyroptosis through the CTCF/DPP4 signaling pathway Front Physiol, 12 (2021), Article 669202

61 M. Yu, B. Su, X. ZhangGardenoside suppresses the pain in rats model of chronic constriction injury by regulating the P2X3 and P2X7 receptors J Recept Signal Transduction, 38 (3) (2018), pp. 198-203

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