ULK1 inhibition promotes oxidative stress–induced differentiation and sensitizes leukemic stem cells to targeted therapy

Ianniciello, A. et al. (2021) ULK1 inhibition promotes oxidative stress–induced differentiation and sensitizes leukemic stem cells to targeted therapy. Science Translational Medicine, 13(613), eabd5016. (doi: 10.1126/scitranslmed.abd5016) (PMID:34586834)

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Inhibition of autophagy has been proposed as a potential therapy for individuals with cancer. However, current lysosomotropic autophagy inhibitors have demonstrated limited efficacy in clinical trials. Therefore, validation of novel specific autophagy inhibitors using robust preclinical models is critical. In chronic myeloid leukemia (CML), minimal residual disease is maintained by persistent leukemic stem cells (LSCs), which drive tyrosine kinase inhibitor (TKI) resistance and patient relapse. Here, we show that deletion of autophagy-inducing kinase ULK1 (unc-51–like autophagy activating kinase 1) reduces growth of cell line and patient-derived xenografted CML cells in mouse models. Using primitive cells, isolated from individuals with CML, we demonstrate that pharmacological inhibition of ULK1 selectively targets CML LSCs ex vivo and in vivo, when combined with TKI treatment. The enhanced TKI sensitivity after ULK1-mediated autophagy inhibition is driven by increased mitochondrial respiration and loss of quiescence and points to oxidative stress–induced differentiation of CML LSCs, proposing an alternative strategy for treating patients with CML.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Scott, Dr Mary and Vetrie, Professor David and Copland, Professor Mhairi and Ianniciello, Ms Angela and Dawson, Ms Amy and Rattigan, Dr Kevin and Michie, Professor Alison and Kalkman, Dr Eric and Nixon, Mr Colin and Dunn, Mrs Karen and Brabcova, Dr Zuzana and Zarou, Martha-Maria and Helgason, Professor Vignir
Authors: Ianniciello, A., Zarou, M. M., Rattigan, K. M., Scott, M., Dawson, A., Dunn, K., Brabcova, Z., Kalkman, E. R., Nixon, C., Michie, A. M., Copland, M., Vetrie, D., Ambler, M., Saxty, B., and Helgason, G. V.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Science Translational Medicine
Publisher:American Association for the Advancement of Science
ISSN (Online):1946-6242
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Science Translational Medicine 13(613): eabd5016
Publisher Policy:Reproduced in accordance with the publisher copyright policy
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
306054Confidence in Concept 2019Anna DominiczakMedical Research Council (MRC)MC_PC_18048MVLS - College Senior Management
307077Targeting Autophagy and Aberrant Metabolism of Leukaemic Stem CellsVignir HelgasonCancer Research UK (CRUK)C57352/A29754CS -Translational Research Centre
301129TASTER (TArgeting STEm cell Resistance) - Defining leukaemic cell clonal architecture to inform and monitor drug responses in the TASTER CML Phase II Clinical TrialMhairi CoplandCancer Research UK (CRUK)C55731/A24896CS - Paul O'Gorman Leukaemia Research Centre