Axl blockade by BGB324 inhibits BCR-ABL tyrosine kinase inhibitor-sensitive and -resistant chronic myeloid leukemia

Ben Batalla, I. et al. (2017) Axl blockade by BGB324 inhibits BCR-ABL tyrosine kinase inhibitor-sensitive and -resistant chronic myeloid leukemia. Clinical Cancer Research, 23(9), pp. 2289-2300. (doi:10.1158/1078-0432.CCR-16-1930) (PMID:27856601)

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Abstract

Purpose:BCR-ABL kinase inhibitors are employed successfully for chronic myeloid leukemia (CML) treatment. However, resistant disease and persistence of BCR-ABL1-independent leukemia stem and progenitor cells (LSPC) remain clinical challenges. The receptor tyrosine kinase Axl can mediate survival and therapy resistance of different cancer cells. We investigated the therapeutic potential of Axl inhibition in CML. Experimental Design:We used primary cells from CML patients and TKI-sensitive and -resistant BCR-ABL1+ CML cell lines and a novel Ponatinib-resistant cell line KCL-22 PonR. We analyzed the effects of genetic and pharmacologic Axl blockade by the small molecule Axl inhibitor BGB324 in vitro and in vivo. In BCR-ABL1 unmutated cells we also investigated BGB324 in combination with imatinib. Results:We demonstrate overexpression of Axl receptor tyrosine kinase in primary cells of CML patients compared to healthy individuals, and a further increase of Axl expression in BCR-ABL TKI-resistant patients. We show that Axl blockage decreased growth of BCR-ABL TKI-sensitive CML cells including CD34+ cells and exerts additive effects with imatinib via inhibition of Stat5 activation. BGB324 also inhibits BCR-ABL TKI-resistant cells, including T315I-mutated and ponatinib-resistant primary cells. BGB324 exerted therapeutic effects in BCR-ABL1 T315I-mutated and ponatinib-resistant preclinical mouse models. Notably, BGB324 does not inhibit BCR-ABL1 and consequently inhibits CML independent of BCR-ABL1 mutational status. Conclusions:Our data show that Axl inhibition has therapeutic potential in BCR-ABL TKI-sensitive as well as resistant CML and support the need for clinical trials.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Jorgensen, Dr Heather and Holyoake, Professor Tessa and Rankin, Dr Stephen and Mitchell, Dr Rebecca
Authors: Ben Batalla, I., Erdmann, R., Jorgensen, H., Mitchell, R., Ernst, T., von Amsberg, G., Schafhausen, P., Velthaus, J. L., Rankin, S., Clark, R. E., Koschmieder, S., Schultze, A., Mitra, S., Vandenberghe, P., Bru mmendorf, T. H., Carmeliet, P., Hochhaus, A., Pantel, K., Bokemeyer, C., Helgason, G. V., Holyoake, T. L., and Loges, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Clinical Cancer Research
Publisher:American Association for Cancer Research
ISSN:1078-0432
ISSN (Online):1557-3265
Published Online:17 November 2016
Copyright Holders:Copyright © 2016 American Association for Cancer Research
First Published:First published in Clinical Cancer Research 23(9): 2289-2300
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
679891Targeting p53, cMyc and PRC2 regulatory hubs: A systematic and stratified approach to deliver new therapeutics for CMLTessa HolyoakeBloodwise (LLR)14033ICS - PAUL O'GORMAN LEUKAEMIA RESEARCH C
542691Development of a flow cytometry service within the Paul O'Gorman Leukaemia Research CentreAlison MichieThe Kay Kendall Leukaemia Fund (KENDALL)KKL501RI CANCER SCIENCES