Interrogation of novel CDK2/9 inhibitor fadraciclib (CYC065) as a potential therapeutic approach for AML

Chantkran, W., Hsieh, Y.-C., Zheleva, D., Frame, S., Wheadon, H. and Copland, M. (2021) Interrogation of novel CDK2/9 inhibitor fadraciclib (CYC065) as a potential therapeutic approach for AML. Cell Death Discovery, 7, 137. (doi: 10.1038/s41420-021-00496-y)

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Abstract

Over the last 50 years, there has been a steady improvement in the treatment outcome of acute myeloid leukemia (AML). However, median survival in the elderly is still poor due to intolerance to intensive chemotherapy and higher numbers of patients with adverse cytogenetics. Fadraciclib (CYC065), a novel cyclin-dependent kinase (CDK) 2/9 inhibitor, has preclinical efficacy in AML. In AML cell lines, myeloid cell leukemia 1 (MCL-1) was downregulated following treatment with fadraciclib, resulting in a rapid induction of apoptosis. In addition, RNA polymerase II (RNAPII)-driven transcription was suppressed, rendering a global gene suppression. Rapid induction of apoptosis was observed in primary AML cells after treatment with fadraciclib for 6–8 h. Twenty-four hours continuous treatment further increased efficacy of fadraciclib. Although preliminary results showed that AML cell lines harboring KMT2A rearrangement (KMT2A-r) are more sensitive to fadraciclib, we found that the drug can induce apoptosis and decrease MCL-1 expression in primary AML cells, regardless of KMT2A status. Importantly, the diversity of genetic mutations observed in primary AML patient samples was associated with variable response to fadraciclib, confirming the need for patient stratification to enable a more effective and personalized treatment approach. Synergistic activity was demonstrated when fadraciclib was combined with the BCL-2 inhibitor venetoclax, or the conventional chemotherapy agents, cytarabine, or azacitidine, with the combination of fadraciclib and azacitidine having the most favorable therapeutic window. In summary, these results highlight the potential of fadraciclib as a novel therapeutic approach for AML.

Item Type:Articles
Additional Information:This research was funded by a PhD studentship from the Royal Thai Government. Additional funding was provided by Cyclacel Ltd. This study was supported by the Glasgow Experimental Cancer Medicine Centre, which is funded by Cancer Research UK and the Chief Scientist’s Office, Scotland. Cell sorting facilities were funded by the Kay Kendall Leukaemia Fund (KKL501) and the Howat Foundation.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Chantkran, Wittawat and Copland, Professor Mhairi and Wheadon, Professor Helen and Hsieh, Dr Ya-Ching
Authors: Chantkran, W., Hsieh, Y.-C., Zheleva, D., Frame, S., Wheadon, H., and Copland, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cell Death Discovery
Publisher:Springer Nature
ISSN:2058-7716
ISSN (Online):2058-7716
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Cell Death Discovery 7: 137
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
174039Glasgow ECMCThomas EvansCancer Research UK (CRUK)C58789/A25174CS - Experimental Therapeutics
163632Development of a flow cytometry service within the Paul O'Gorman Leukaemia Research CentreAlison MichieThe Kay Kendall Leukaemia Fund (KENDALL)KKL501CS - Paul O'Gorman Leukaemia Research Centre