AKT/mTORC2 inhibition activates FOXO1 function in CLL cells reducing B cell receptor-mediated survival

Cosimo, E. et al. (2019) AKT/mTORC2 inhibition activates FOXO1 function in CLL cells reducing B cell receptor-mediated survival. Clinical Cancer Research, 25(5), pp. 1574-1587. (doi: 10.1158/1078-0432.CCR-18-2036) (PMID:30559170) (PMCID:PMC6398589)

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Purpose: To determine whether inhibition of mechanistic target of rapamycin (mTOR) kinase-mediated signaling represents a valid therapeutic approach for chronic lymphocytic leukemia (CLL). Experimental Design: Stratification of mTOR activity was carried out in primary CLL patient 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 p4EBP1T37/46 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 FOXO1T24 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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Michie, Professor Alison and Moles, Mr Michael and Mccaig, Dr Alison and Dunn, Mrs Karen and Cosimo, Dr Emilio and Holroyd, Dr Ailsa and Tarafdar, Ms Anuradha and Malik, Natasha and Hay, Dr Jodie and Sansom, Professor Owen
Authors: Cosimo, E., Tarafdar, A., Moles, M. W., Holroyd, A. K., Malik, N., Catherwood, M. A., Hay, J., Dunn, K. M., Macdonald, A. M., Guichard, S. M., O'Rourke, D. M., Leach, M. T., Sansom, O. J., Cosulich, S. C., McCaig, A. M., and Michie, A. M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Clinical Cancer Research
Publisher:American Association for Cancer Research
ISSN (Online):1557-3265
Published Online:17 December 2018
Copyright Holders:Copyright © 2018 American Association for Cancer Research
First Published:First published in Clinical Cancer Research 25(5): 1574-1587
Publisher Policy:Reproduced in accordance with the publisher copyright policy
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
600561MICA: Determining the therapeutic potential of targeting mTORC-1/2 in chronic lymphocytic leukaemia - a pre-clinical studyAlison MichieMedical Research Council (MRC)MR/K014854/1ICS - PAUL O'GORMAN LEUKAEMIA RESEARCH C
698661Elucidating the role of individual mTor complexes in the development and progression of chronic lymphocytic leukaemiaAlison MichieBloodwise (BLOODWIS)15041ICS - PAUL O'GORMAN LEUKAEMIA RESEARCH C
542691Development of a flow cytometry service within the Paul O'Gorman Leukaemia Research CentreAlison MichieThe Kay Kendall Leukaemia Fund (KENDALL)KKL501RI CANCER SCIENCES
591941Regulation of PKC-beta gene expression in in CLL cells.Alison MichieBloodwise (LRF)13012ICS - PAUL O'GORMAN LEUKAEMIA RESEARCH C
653711Elucidating the role of mTor kinase signalling in chronic lymphocytic leukaemiaAilsa HolroydThe Kay Kendall Leukaemia Fund (KENDALL)KKL838RI CANCER SCIENCES