Advances of signal transducer and activator of transcription 3 inhibitors in acute myeloid leukemia (Review)
- Authors:
- Hui Cheng
- Li Chen
- Chongmei Huang
-
Affiliations: Department of Hematology, First Affiliated Hospital, Naval Medical University, Shanghai 200433, P.R. China, Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China - Published online on: January 8, 2025 https://doi.org/10.3892/ol.2025.14881
- Article Number: 134
-
Copyright: © Cheng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
This article is mentioned in:
Abstract
 |
 |
 |
|
Shimony S, Stahl M and Stone RM: Acute myeloid leukemia: 2023 Update on diagnosis, risk-stratification, and management. Am J Hematol. 98:502–526. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Colmone A, Amorim M, Pontier AL, Wang S, Jablonski E and Sipkins DA: Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells. Science. 322:1861–1865. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
De Kouchkovsky I and Abdul-Hay M: ‘Acute myeloid leukemia: A comprehensive review and 2016 update’. Blood Cancer J. 6:e4412016. View Article : Google Scholar : PubMed/NCBI | |
|
Juliusson G, Antunovic P, Derolf A, Lehmann S, Möllgård L, Stockelberg D, Tidefelt U, Wahlin A and Höglund M: Age and acute myeloid leukemia: Real world data on decision to treat and outcomes from the Swedish acute leukemia registry. Blood. 113:4179–4187. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, et al: Diagnosis and management of AML in adults: 2022 ELN recommendations from an international expert panel. Blood. 129:424–447. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
National Institute of Health, . Surveillance and Epidemiology, End Results (SEER) US county populations 1969–2020. February;2022.Available from. www.seer.cancer.gov/popdataNovember 9–2022 | |
|
DiNardo CD, Erba HP, Freeman SD and Wei AH: Acute myeloid leukaemia. Lancet. 401:2073–2086. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Ihle JN: The Stat family in cytokine signaling. Curr Opin Cell Biol. 13:211–217. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Levy DE and Lee CK: What does Stat3 do? J Clin Invest. 109:1143–1148. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Haura EB, Turkson J and Jove R: Mechanisms of disease: Insights into the emerging role of signal transducers and activators of transcription in cancer. Nat Clin Pract Oncol. 2:315–324. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Aigner P, Just V and Stoiber D: STAT3 isoforms: Alternative fates in cancer? Cytokine. 118:27–34. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang HX, Yang PL, Li EM and Xu LY: STAT3beta, a distinct isoform from STAT3. Int J Biochem Cell Biol. 110:130–139. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Hendry L and John S: Regulation of STAT signaling by proteolytic processing. Eur J Biochem. 71:4613–4620. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Johnson DE, O'Keefe RA and Grandis JR: Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 15:234–248. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Xia Z, Baer MR, Block AW, Baumann H and Wetzler M: Expression of signal transducers and activators of transcription proteins in acute myeloid leukemia blasts. Cancer Res. 58:3173–3180. 1998.PubMed/NCBI | |
|
Benekli M, Xia Z, Donohue KA, Ford LA, Pixley LA, Baer MR, Baumann H and Wetzler M: Constitutive activity of signal transducer and activator of transcription 3 protein in acute myeloid leukemia blasts is associated with short disease-free survival. Blood. 99:252–257. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Chen Y, Ji M, Zhang S, Xue N, Xu H, Lin S and Chen X: Bt354 as a new STAT3 signaling pathway inhibitor against triple negative breast cancer. J Drug Target. 26:920–930. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Geiger JL, Grandis JR and Bauman JE: The STAT3 pathway as a therapeutic target in head and neck cancer: Barriers and innovations. Oral Oncol. 56:84–92. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Bharadwaj U, Eckols TK, Xu X, Kasembeli MM, Chen Y, Adachi M, Song Y, Mo Q, Lai SY and Tweardy DJ: Small-molecule inhibition of STAT3 in radioresistant head and neck squamous cell carcinoma. Oncotarget. 7:26307–26330. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Park JH, van Wyk H, McMillan DC, Quinn J, Clark J, Roxburgh CSD, Horgan PG and Edwards J: Signal transduction and activator of transcription-3 (STAT3) in patients with colorectal cancer: Associations with the phenotypic features of the tumor and host. Clin Cancer Res. 23:1698–1709. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Redell MS, Ruiz MJ, Alonzo TA, Gerbing RB and Tweardy DJ: Stat3 signaling in acute myeloid leukemia: Ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitor. Blood. 117:5701–5709. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Minus MB, Liu W, Vohidov F, Kasembeli MM, Long X, Krueger MJ, Stevens A, Kolosov MI, Tweardy DJ, Sison EAR, et al: Rhodium(II) proximity-labeling identifies a novel target site on STAT3 for inhibitors with potent anti-leukemia activity. Angew Chem Int Ed Engl. 54:13085–13089. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Yu H, Lee H, Herrmann A, Buettner R and Jove R: Revisiting STAT3 signalling in cancer: New and unexpected biological functions. Nat Rev Cancer. 14:736–746. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Takeda K and Akira S: STAT family of transcription factors in cytokine-mediated biological responses. Cytokine Growth Factor Rev. 11:199–207. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Rane SG and Reddy EP: JAKs, STATs and Src kinases in hematopoiesis. Oncogene. 21:3334–3358. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Bruserud Ø, Nepstad I, Hauge M, Hatfield KJ and Reikvam H: STAT3 as a possible therapeutic target in human malignancies: Lessons from acute myeloid leukemia. Expert Rev Hematol. 8:29–41. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Sellier H, Rébillard A, Guette C, Barré B and Coqueret O: How should we define STAT3 as an oncogene and as a potential target for therapy? JAKSTAT. 2:e247162013.PubMed/NCBI | |
|
Frank DA: STAT3 as a central mediator of neoplastic cellular transformation. Cancer Lett. 251:199–210. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Bar-Natan M, Nelson EA, Xiang M and Frank DA: STAT signaling in the pathogenesis and treatment of myeloid malignancies. JAKSTAT. 1:55–64. 2012.PubMed/NCBI | |
|
Hutchins AP, Diez D and Miranda-Saavedra D: Genomic and computational approaches to dissect the mechanisms of STAT3′s universal and cell type-specific functions. JAKSTAT. 2:e250972013.PubMed/NCBI | |
|
Yu H and Jove R: The STATs of cancer-new molecular targets come of age. Nat Rev Cancer. 4:97–105. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Spiekermann K, Biethahn S, Wilde S, Hiddemann W and Alves F: Constitutive activation of STAT transcription factors in acute myelogenous leukemia. Eur J Haematol. 67:63–71. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Spiekermann K, Pau M, Schwab R, Schmieja K, Franzrahe S and Hiddemann W: Constitutive activation of STAT3 and STAT5 is induced by leukemic fusion proteins with protein tyrosine kinase activity and is sufficient for transformation of hematopoietic precursor cells. Exp Hematol. 30:262–271. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Hankey PA: Regulation of hematopoietic cell development and function by Stat3. Front Biosci (Landmark Ed). 14:5273–5290. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Aoki Y, Feldman GM and Tosato G: Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma. Blood. 101:1535–1542. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Koskela HLM, Eldfors S, Ellonen P, van Adrichem AJ, Kuusanmäki H, Andersson EI, Lagström S, Clemente MJ, Olson T, Jalkanen SE, et al: Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med. 366:1905–1913. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Pilati C, Amessou M, Bihl MP, Balabaud C, Nhieu JT, Paradis V, Nault JC, Izard T, Bioulac-Sage P, Couchy G, et al: Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas. J Exp Med. 208:1359–1366. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Xia Z, Sait SN, Baer MR, Barcos M, Donohue KA, Lawrence D, Ford LA, Block AM, Baumann H and Wetzler M: Truncated STAT proteins are prevalent at relapse of acute myeloid leukemia. Leuk Res. 25:473–482. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Lee HJ, Zhuang G, Cao Y, Du P, Kim HJ and Settleman J: Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell. 26:207–221. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Schust J, Sperl B, Hollis A, Mayer TU and Berg T: Stattic: A small-molecule inhibitor of STAT3 activation and dimerization. Chem Biol. 13:1235–1242. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Luo Y, Lu Y, Long B, Lin Y, Yang Y, Xu Y, Zhang X and Zhang J: Blocking DNA damage repair may be involved in stattic (STAT3 inhibitor)-induced FLT3-ITD AML cell apoptosis. Front Cell Dev Biol. 9:6370642021. View Article : Google Scholar : PubMed/NCBI | |
|
Goldstein M and Kastan MB: The DNA damage response: Implications for tumor responses to radiation and chemotherapy. Annu Rev Med. 66:129–143. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Genini D, Brambilla L, Laurini E, Merulla J, Civenni G, Pandit S, D'Antuono R, Perez L, Levy DE, Pricl S, et al: Mitochondrial dysfunction induced by a SH2 domain-targeting STAT3 inhibitor leads to metabolic synthetic lethality in cancer cells. Proc Natl Acad Sci USA. 114:E4924–E4933. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Ogura M, Uchida T, Terui Y, Hayakawa F, Kobayashi Y, Taniwaki M, Takamatsu Y, Naoe T, Tobinai K, Munakata W, et al: Phase I study of OPB-51602, an oral inhibitor of signal transducer and activator of transcription 3, in patients with relapsed/refractory hematological malignancies. Cancer Sci. 106:896–901. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Hubbard JM and Grothey A: Napabucasin: An update on the first-in-class cancer stemness inhibitor. Drugs. 77:1091–1103. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Bi S, Chen K, Feng L, Fu G, Yang Q, Deng M, Zhao H, Li Z, Yu L, Fang Z and Xu B: Napabucasin (BBI608) eliminate AML cells in vitro and in vivo via inhibition of Stat3 pathway and induction of DNA damage. Eur J Pharmacol. 855:252–261. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Zhou H, Bai L, Xu R, Zhao Y, Chen J, McEachern D, Chinnaswamy K, Wen B, Dai L, Kumar P, et al: Structure-based discovery of SD-36 as a potent, selective, and efficacious PROTAC degrader of STAT3 protein. J Med Chem. 62:11280–11300. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Gadd MS, Testa A, Lucas X, Chan KH, Chen W, Lamont DJ, Zengerle M and Ciulli A: Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat Chem Biol. 13:514–521. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Dale B, Cheng M, Park KS, Kaniskan HÜ, Xiong Y and Jin J: Advancing targeted protein degradation for cancer therapy. Nat Rev Cancer. 21:638–654. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Bai L, Zhou H, Xu R, Zhao Y, Chinnaswamy K, McEachern D, Chen J, Yang CY, Liu Z, Wang M, et al: A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo. Cancer Cell. 36:498–511.e17. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Mo J, Deng L, Peng K, Ouyang S, Ding W, Lou L, Lin Z, Zhu J, Li J, Zhang Q, et al: Targeting STAT3-VISTA axis to suppress tumor aggression and burden in acute myeloid leukemia. J Hematol Oncol. 16:152023. View Article : Google Scholar : PubMed/NCBI | |
|
Yuan L, Tatineni J, Mahoney KM and Freeman GJ: VISTA: A mediator of quiescence and a promising target in cancer immunotherapy. Trends Immunol. 42:209–227. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Deng L, Mo J, Zhang Y, Peng K, Li H, Ouyang S, Feng Z, Fang W, Wei J, Rong D, et al: Boronic acid: A novel pharmacophore targeting Src homology 2 (SH2) domain of STAT3. J Med Chem. 65:13094–13111. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Hossain DMH, Dos Santos C, Zhang Q, Kozlowska A, Liu H, Gao C, Moreira D, Swiderski P, Jozwiak A, Kline J, et al: Leukemia cell-targeted STAT3 silencing and TLR9 triggering generate systemic antitumor immunity. Blood. 123:15–25. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Krieg AM: Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene. 27:161–167. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang Q, Hossain DMS, Duttagupta P, Moreira D, Zhao X, Won H, Buettner R, Nechaev S, Majka M, Zhang B, et al: Serum-resistant CpG-STAT3 decoy for targeting survival and immune checkpoint signaling in acute myeloid leukemia. Blood. 127:1687–1700. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Hong D, Kurzrock R, Kim Y, Woessner R, Younes A, Nemunaitis J, Fowler N, Zhou T, Schmidt J, Jo M, et al: AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. Sci Transl Med. 7:314ra1852015. View Article : Google Scholar : PubMed/NCBI | |
|
Shastri A, Choudhary G, Teixeira M, Gordon-Mitchell S, Ramachandra N, Bernard L, Bhattacharyya S, Lopez R, Pradhan K, Giricz O, et al: Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells. J Clin Invest. 128:5479–5488. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Chen X, Chen HY, Chen ZD, Gong JN and Chen CYC: A novel artificial intelligence protocol for finding potential inhibitors of acute myeloid leukemia. J Mater Chem B. 8:2063–2081. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Chen C, Wang L, Li L, Wang A, Huang T, Hu J, Zhao M, Liu F, Qi S, Hu C, et al: Network-based analysis with primary cells reveals drug response landscape of acute myeloid leukemia. Exp Cell Res. 393:1120542020. View Article : Google Scholar : PubMed/NCBI | |
|
Dai T, Zhang L, Dai X, Zhang X, Lu B, Zheng Y, Shen D, Yan Y, Ji C, Yu J and Sun L: Multimode participation of traditional Chinese medicine in the treatment of COVID-19. Integr Med Res. 10 (Suppl 1):S1007812021. View Article : Google Scholar : PubMed/NCBI | |
|
Chledzik S, Strawa J, Matuszek K and Nazaruk J: Pharmacological effects of scutellarin, an active component of genus scutellaria and erigeron: A systematic review. Am J Chin Med. 46:319–337. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
You L, Zhu H, Wang C, Wang F, Li Y, Li Y, Wang Y and He B: Scutellarin inhibits Hela cell growth and glycolysis by inhibiting the activity of pyruvate kinase M2. Bioorg Med Chem Lett. 27:5404–5408. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Ke Y, Bao T, Wu X, Tang H, Wang Y, Ge J, Fu B, Meng X, Chen L, Zhang C, et al: Scutellarin suppresses migration and invasion of human hepatocellular carcinoma by inhibiting the STAT3/Girdin/Akt activity. Biochem Biophys Res Commun. 483:509–515. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Chen J, Cai YF, Shao M and Cong H: Effect of scutellarin on proliferation of acute myeloid leukemia cells and its related mechanism. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 31:358–363. 2023.(In Chinese). PubMed/NCBI | |
|
Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, Bejar R, Berti E, Busque L, Chan JKC, et al: The 5th of the World Health Organization classifcation of haematolymphoid tumours: Myeloid and histiocytic/dendritic neoplasms. Leukemia. 36:1703–1719. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Arber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka HM, Wang SA, Bagg A, Barbui T, Branford S, et al: International consensus classification of myeloid neoplasms and acute leukemias: Integrating morphologic, clinical, and genomic data. Blood. 140:1200–1228. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
DiNardo KW, LeBlanc TW and Chen H: Novel agents and regimens in acute myeloid leukemia: Latest updates from 2022 ASH annual meeting. J Hematol Oncol. 16:172023. View Article : Google Scholar : PubMed/NCBI |
