دورية أكاديمية
AKT/mTORC2 Inhibition Activates FOXO1 Function in CLL Cells Reducing B-Cell Receptor-Mediated Survival.
| العنوان: | AKT/mTORC2 Inhibition Activates FOXO1 Function in CLL Cells Reducing B-Cell Receptor-Mediated Survival. |
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| المؤلفون: | Cosimo E; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom., Tarafdar A; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom., Moles MW; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom., Holroyd AK; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom., Malik N; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom., Catherwood MA; Department of Haematology, Belfast City Hospital, Belfast, United Kingdom., Hay J; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom., Dunn KM; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom., Macdonald AM; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom., Guichard SM; Forma Therapeutics, Watertown, Massachusetts., O'Rourke D; Department of Histopathology, Belfast City Hospital, Belfast, United Kingdom., Leach MT; Department of Haematology, Gartnavel General Hospital, Glasgow, United Kingdom., Sansom OJ; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.; Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, United Kingdom., Cosulich SC; Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom., McCaig AM; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.; Royal Alexandra Hospital, Paisley, United Kingdom., Michie AM; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom. Alison.Michie@glasgow.ac.uk. |
| المصدر: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2019 Mar 01; Vol. 25 (5), pp. 1574-1587. Date of Electronic Publication: 2018 Dec 17. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-3265 (Electronic) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Denville, NJ : The Association, c1995- |
| مواضيع طبية MeSH: | Forkhead Box Protein O1/*metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/*metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/*mortality , Mechanistic Target of Rapamycin Complex 2/*antagonists & inhibitors , Protein Kinase Inhibitors/*pharmacology , Proto-Oncogene Proteins c-akt/*antagonists & inhibitors , Receptors, Antigen, B-Cell/*metabolism, Animals ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Disease Models, Animal ; Drug Synergism ; Female ; Forkhead Box Protein O1/genetics ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Male ; Mechanistic Target of Rapamycin Complex 2/metabolism ; Mice ; Mice, Transgenic ; Prognosis ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction/drug effects ; Treatment Outcome ; Xenograft Model Antitumor Assays |
| مستخلص: | Purpose: To determine whether inhibition of mTOR kinase-mediated signaling represents a valid therapeutic approach for chronic lymphocytic leukemia (CLL). Experimental Design: Stratification of mTOR activity was carried out in patients with primary CLL samples and an aggressive CLL-like mouse model. The potency of dual mTOR inhibitor AZD8055 to induce apoptosis in primary CLL cells was assessed in the presence/absence of B-cell receptor (BCR) ligation. Furthermore, we addressed the molecular and functional impact of dual mTOR inhibition in combination with BTK inhibitor ibrutinib. Results: Differential regulation of basal mTORC1 activity was observed in poor prognostic CLL samples, with elevated p4EBP1 T37/46 and decreased p70S6 kinase activity, suggesting that dual mTORC1/2 inhibitors may exhibit improved response in poor prognostic CLL compared with rapalogs. AZD8055 treatment of primary CLL cells significantly reduced CLL survival in vitro compared with rapamycin, preferentially targeting poor prognostic subsets and overcoming BCR-mediated survival advantages. Furthermore, AZD8055, and clinical analog AZD2014, significantly reduced CLL tumor load in mice. AKT substrate FOXO1, while overexpressed in CLL cells of poor prognostic patients in LN biopsies, peripheral CLL cells, and mouse-derived CLL-like cells, appeared to be inactive. AZD8055 treatment partially reversed FOXO1 inactivation downstream of BCR crosslinking, significantly inhibiting FOXO1 T24 phosphorylation in an mTORC2-AKT-dependent manner, to promote FOXO1 nuclear localization, activity, and FOXO1-mediated gene regulation. FOXO1 activity was further significantly enhanced on combining AZD8055 with ibrutinib. Conclusions: Our studies demonstrate that dual mTOR inhibitors show promise as future CLL therapies, particularly in combination with ibrutinib. (©2018 American Association for Cancer Research.) |
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| معلومات مُعتمدة: | 21139 United Kingdom CRUK_ Cancer Research UK; G0701354 United Kingdom MRC_ Medical Research Council; MR/K014854/1 United Kingdom MRC_ Medical Research Council |
| المشرفين على المادة: | 0 (FOXO1 protein, human) 0 (Forkhead Box Protein O1) 0 (Protein Kinase Inhibitors) 0 (Receptors, Antigen, B-Cell) EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) |
| تواريخ الأحداث: | Date Created: 20181219 Date Completed: 20200408 Latest Revision: 20240210 |
| رمز التحديث: | 20240210 |
| مُعرف محوري في PubMed: | PMC6398589 |
| DOI: | 10.1158/1078-0432.CCR-18-2036 |
| PMID: | 30559170 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1557-3265 |
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| DOI: | 10.1158/1078-0432.CCR-18-2036 |