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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131767.pdf - Accepted Version 3MB |
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: | Rankin, Dr Stephen and Mitchell, Dr Rebecca and Jorgensen, Dr Heather and Holyoake, Professor Tessa |
| 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 > School 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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