Small molecule STAT3/5 inhibitors exhibit therapeutic potential in acute myeloid leukemia and extra-nodal natural killer/T cell lymphoma
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Abstract Background: The oncogenic transcription factors STAT3, STAT5A and STAT5B are essential to steer hematopoiesis and immunity, but their enhanced expression and activation drives the development or progression of blood cancers, such as AML and NKCL. Current therapeutic strategies to inhibit STAT3/5 activity focus on blocking upstream tyrosine kinases, but frequently occurring resistance often leads to disease relapse, emphasizing the need for new STAT3/5 targeted therapies. Methods: Cytotoxicity assays were used to assess the impact of our STAT3/5 inhibitors JPX-0700/JPX-0750 on cell viability alone, or in combination with approved antineoplastic agents, in NKCL or AML cancer cell lines and primary AML patient samples. To identify genetic abnormalities of cell lines, we utilized array comparative genome hybridization. Western blotting and flow cytometry were employed to elucidate the mechanisms of the inhibitors on cell viability, cell cycle and STAT3/5 downstream signaling. In order to evaluate the effectiveness and safety of these compounds in vivo, we established AML and NKCL mouse xenografts and administered daily intraperitoneal injections of the inhibitors. Results: Our STAT3/5 degraders selectively reduced STAT3/5 activation and total protein levels, as well as downstream target oncogene expression, exhibiting nanomolar to low micromolar efficacy in inducing cell death in AML/NKCL cell lines and AML patient samples. We found that both AML/NKCL cells hijack STAT3/5 signaling through either upstream activating mutations in tyrosine kinases, activating gain-of-function mutations in STAT3, mutational loss of negative STAT regulators, or genetic gains in anti-apoptotic, pro-proliferative or epigenetic-modifying STAT3/5 targets, emphasizing STAT3/5 as valid targets in these diseases. JPX-0700/-0750 treatment reduced leukemic cell growth in human AML or NKCL xenograft mouse models, without adverse side effects. Additionally, we observed synergistic cell death induced by JPX-0700/-0750 upon combinatorial use with approved chemotherapeutics in AML/NKCL cell lines and AML patient blasts. Conclusion: We demonstrate the effectiveness of dual pharmacologic inhibition of phospho- and total STAT3/5 by JPX inhibitors in AML and NKCL, emphasizing their essential roles in initiating and driving these cancers. These potent small molecule degraders of STAT3/5 could propel further clinical development and may emerge as highly effective combinatorial partners for the treatment of AML and NKCL patients.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Small molecule STAT3/5 inhibitors exhibit therapeutic potential in acute myeloid leukemia and extra-nodal natural killer/T cell lymphoma
- Date Crossref
- 18/10/2023
- Éditeur
- Research Square Platform LLC
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University of Veterinary Medicine Vienna Unit of Functional Cancer Genomics pays non établi dans la noticeUniversité ou école supérieure
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University of Toronto Department of Chemical and Physical Sciences pays non établi dans la noticeUniversité ou école supérieure
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University of Helsinki Hematology Research Unit Helsinki pays non établi dans la noticeUniversité ou école supérieure
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Helsinki University Hospital pays non établi dans la noticeÉtablissement de santé
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Institute for Molecular Medicine Finland pays non établi dans la noticeStructure de recherche
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Vienna General Hospital pays non établi dans la noticeÉtablissement de santé
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Medical University of Vienna Department of Pediatric and Adolescent Surgery pays non établi dans la noticeUniversité ou école supérieure
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Comprehensive Cancer Center Vienna pays non établi dans la noticeÉtablissement de santé
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Center for Cancer Research pays non établi dans la noticeStructure de recherche
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Leipzig University pays non établi dans la noticeUniversité ou école supérieure
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a Centessa Company Janpix pays non établi dans la noticeEntreprise
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University of Leipzig Department of Hematology pays non établi dans la noticeUniversité ou école supérieure
Unit of Functional Cancer Genomics — University of Veterinary Medicine Vienna, Department of Chemical and Physical Sciences — University of Toronto et Hematology Research Unit Helsinki — University of Helsinki, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.