Kill one bird with two stones: potential efficacy of BCR-ABL and autophagy inhibition in CML

Helgason, G. V. , Karvela, M. and Holyoake, T. L. (2011) Kill one bird with two stones: potential efficacy of BCR-ABL and autophagy inhibition in CML. Blood, 118(8), pp. 2035-2043. (doi: 10.1182/blood-2011-01-330621)



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The introduction of imatinib in the treatment of chronic myeloid leukaemia (CML) represents the most successful example of targeted therapy in human cancer. However, leukaemic stem cells (LSCs) are insensitive to tyrosine kinase inhibitors (TKIs) and contribute to disease persistence by representing a reservoir of self-renewing cells that replenish the disease upon drug discontinuation. This has re-focused the interest of scientists towards drug combinations i.e. treating with TKIs and simultaneously targeting alternative survival mechanisms. One candidate target mechanism is autophagy, a cellular recycling process that acts as a cytoprotective shield in CML cells in response to TKI-induced stress and in other cancer cells surviving in an inhospitable microenvironment. On that basis, inhibition of autophagy has now become an exciting option for combination treatment in cancer and clinical trials have been initiated in solid and haemopoietic tumours such as CML, chronic lymphocytic leukaemia (CLL) and multiple myeloma. This review describes the biology of CML and elucidates how the molecular driver BCR-ABL led to the development of TKIs. We then discuss the molecular regulation of autophagy and the potential for autophagy inhibition as the next step in our attempt to tackle the problem of CML persistence to offer a curative option.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Holyoake, Professor Tessa and Helgason, Professor Vignir and Karvela, Miss Maria
Authors: Helgason, G. V., Karvela, M., and Holyoake, T. L.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Blood
Publisher:American Society of Hematology
ISSN (Online):1528-0020
Published Online:21 June 2011
Copyright Holders:Copyright © 2011 American Society of Hematology
First Published:First published in Blood 118(8):2035-2043
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
439231Is Bcr-Able expression relevant for the survival of cancer stem cells in chronic myeloid leukaemiaTessa HolyoakeMedical Research Council (MRC)G0600782Institute of Cancer Sciences
503111A randomised Phase II trial of Imatinib (IM) versus hydroxychloroquine (HCQ) with IM for patients with chronic myeloid leukaemia (CML) in cytogenic response (CyR)- CHOICESTessa HolyoakeMedical Research Council (MRC)G0900882Institute of Cancer Sciences