BH3 mimetics in combination with nilotinib or ponatinib represent a promising therapeutic strategy in blast phase chronic myeloid leukemia

Parry, N., Busch, C., Aßmann, V., Cassels, J., Hair, A., Helgason, G. V. , Wheadon, H. and Copland, M. (2022) BH3 mimetics in combination with nilotinib or ponatinib represent a promising therapeutic strategy in blast phase chronic myeloid leukemia. Cell Death Discovery, 8, 457. (doi: 10.1038/s41420-022-01211-1) (PMID:36379918) (PMCID:PMC9666353)

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Dysregulation of the BCL-2 family is implicated in protecting chronic myeloid leukemia (CML) cells from intracellular damage and BCR::ABL1-inhibition with tyrosine kinase inhibitors (TKIs) and may be a viable therapeutic target in blast phase (BP-)CML, for which treatment options are limited. BH3 mimetics, a class of small molecule inhibitors with high-specificity against the prosurvival members of the BCL-2 family, have displayed clinical promise in the treatment of chronic lymphocytic and acute myeloid leukemia as single agents and in combination with standard-of-care therapies. Here we present the first comparison of inhibition of BCL-2 prosurvival proteins BCL-2, BCL-xL and MCL-1 in combination with a second or third generation TKI, crucially with comparisons drawn between myeloid and lymphoid BP-CML samples. Co-treatment of four BP-CML cell lines with the TKIs nilotinib or ponatinib and either BCL-2 (venetoclax), MCL-1 (S63845) or BCL-xL (A-1331852) inhibitors resulted in a synergistic reduction in cell viability and increase in phosphatidylserine (PS) presentation. Nilotinib with BH3 mimetic combinations in myeloid BP-CML patient samples triggered increased induction of apoptosis over nilotinib alone, and a reduction in colony-forming capacity and CD34+ fraction, while this was not the case for lymphoid BP-CML samples tested. While some heterogeneity in apoptotic response was observed between cell lines and BP-CML patient samples, the combination of BCL-xL and BCR::ABL1 inhibition was consistently effective in inducing substantial apoptosis. Further, while BH3 mimetics showed little efficacy as single agents, dual-inhibition of BCL-2 prosurvival proteins dramatically induced apoptosis in all cell lines tested and in myeloid BP-CML patient samples compared to healthy donor samples. Gene expression and protein level analysis suggests a protective upregulation of alternative BCL-2 prosurvival proteins in response to BH3 mimetic single-treatment in BP-CML. Our results suggest that BH3 mimetics represent an interesting avenue for further exploration in myeloid BP-CML, for which alternative treatment options are desperately sought.

Item Type:Articles
Additional Information:Funding: This work was funded by a PhD Studentship from the University of Glasgow and by the Wellcome Trust Institutional Strategic Support Fund [204820/Z/16/Z] and was supported by the Glasgow Experimental Cancer Medicine Centre which is funded by Cancer Research UK (C58789/A25174) and the Chief Scientist’s Office, Scotland. Flow cytometry facilities were funded by the Howat Foundation.
Glasgow Author(s) Enlighten ID:Parry, Narissa and Busch, Caroline and Assmann, Victoria Desiree and Hair, Dr Alan and Helgason, Professor Vignir and Copland, Professor Mhairi and Cassels, Miss Jennifer and Wheadon, Professor Helen
Authors: Parry, N., Busch, C., Aßmann, V., Cassels, J., Hair, A., Helgason, G. V., Wheadon, H., and Copland, M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cell Death Discovery
Publisher:Springer Nature
ISSN (Online):2058-7716
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Cell Death Discovery 8: 457
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
173707Institutional Strategic Support Fund (2016)Anna DominiczakWellcome Trust (WELLCOTR)204820/Z/16/ZInstitute of Cardiovascular & Medical Sciences
174039Glasgow ECMCThomas EvansCancer Research UK (CRUK)C58789/A25174CS - Experimental Therapeutics