Activity of Bruton's tyrosine-kinase inhibitor ibrutinib in patients with CD117-positive acute myeloid leukaemia: a mechanistic study using patient-derived blast cells

Rushworth, Stuart A., Pillinger, Genevra, Abdul-Aziz, Amina, Piddock, Rachel, Shafat, Manar S., Murray, Megan Y., Zaitseva, Lyubov, Lawes, Matthew J., MacEwan, David J. and Bowles, Kristian M. (2015) Activity of Bruton's tyrosine-kinase inhibitor ibrutinib in patients with CD117-positive acute myeloid leukaemia: a mechanistic study using patient-derived blast cells. The Lancet Haematology, 2 (5). e204-e211.

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Abstract

Background: Roughly 80% of patients with acute myeloid leukaemia have high activity of Bruton's tyrosine-kinase (BTK) in their blast cells compared with normal haemopoietic cells, rendering the cells sensitive to the oral BTK inhibitor ibrutinib in vitro. We aimed to develop the biological understanding of the BTK pathway in acute myeloid leukaemia to identify clinically relevant diagnostic information that might define a subset of patients that should respond to ibrutinib treatment. Methods: We obtained acute myeloid leukaemia blast cells from unselected patients attending our UK hospital between Feb 19, 2010, and Jan 20, 2014. We isolated primary acute myeloid leukaemia blast cells from heparinised blood and human peripheral blood mononuclear cells to establish the activity of BTK in response to CD117 activation. Furthermore, we investigated the effects of ibrutinib on CD117-induced BTK activation, downstream signalling, adhesion to primary bone-marrow mesenchymal stromal cells, and proliferation of primary acute myeloid leukaemia blast cells. We used the Mann-Whitney U test to compare results between groups. Findings: We obtained acute myeloid leukaemia blast cells from 29 patients. Ibrutinib significantly inhibited CD117-mediated proliferation of primary acute myeloid leukaemia blast cells (p=0·028). CD117 activation increased BTK activity by inducing phosphorylated BTK in patients with CD117-positive acute myeloid leukaemia. Furthermore, ibrutinib inhibited CD117-induced activity of BTK and downstream kinases at a concentration of 100 nM or more. CD117-mediated adhesion of CD117-expressing blast cells to bone-marrow stromal cells was significantly inhibited by Ibrutinib at 500 nM (p=0·028) Interpretation: As first-in-man clinical trials of ibrutinib in patients with acute myeloid leukaemia commence, the data suggest not all patients will respond. Our findings show that BTK has specific pro-tumoural biological actions downstream of surface CD117 activation, which are inhibited by ibrutinib. Accordingly, we propose that patients with acute myeloid leukaemia whose blast cells express CD117 should be considered for forthcoming clinical trials of ibrutinib.

Item Type: Article
Additional Information: Working title: Activity of ibrutinib, a BTK inhibitor, in patients with CD117 positive acute myeloid leukaemia - a pre-clinical study
Uncontrolled Keywords: acute myeloid leukaemia,bruton's tyrosine kinas,c-kit,cd117,ibrutinib
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Faculty of Science > School of Biological Sciences
Depositing User: Pure Connector
Date Deposited: 28 Sep 2015 16:18
Last Modified: 22 Jul 2020 00:20
URI: https://ueaeprints.uea.ac.uk/id/eprint/54512
DOI: 10.1016/S2352-3026(15)00046-0

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