Abcg2 overexpression represents a novel mechanism for acquired resistance to the multi-kinase inhibitor Danusertib in BCR-ABL-positive cells in vitro.

Balabanov, S. et al. (2011) Abcg2 overexpression represents a novel mechanism for acquired resistance to the multi-kinase inhibitor Danusertib in BCR-ABL-positive cells in vitro. PLoS ONE, 6(4), e19164.

Abstract

The success of Imatinib (IM) therapy in chronic myeloid leukemia (CML) is compromised by the development of IM resistance and by a limited IM effect on hematopoietic stem cells. Danusertib (formerly PHA-739358) is a potent pan-aurora and ABL kinase inhibitor with activity against known BCR-ABL mutations, including T315I. Here, the individual contribution of both signaling pathways to the therapeutic effect of Danusertib as well as mechanisms underlying the development of resistance and, as a consequence, strategies to overcome resistance to Danusertib were investigated. Starting at low concentrations, a dose-dependent inhibition of BCR-ABL activity was observed, whereas inhibition of aurora kinase activity required higher concentrations, pointing to a therapeutic window between the two effects. Interestingly, the emergence of resistant clones during Danusertib exposure in vitro occurred considerably less frequently than with comparable concentrations of IM. In addition, Danusertib-resistant clones had no mutations in BCR-ABL or aurora kinase domains and remained IM-sensitive. Overexpression of Abcg2 efflux transporter was identified and functionally validated as the predominant mechanism of acquired Danusertib resistance <i>in vitro</i>. Finally, the combined treatment with IM and Danusertib significantly reduced the emergence of drug resistance <i>in vitro</i>, raising hope that this drug combination may also achieve more durable disease control <i>in vivo</i>.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Holyoake, Professor Tessa
• Authors: Balabanov, S., Gontarewicz, A., Keller, G., Raddrizzani, L., Braig, M., Bosotti, R., Moll, J., Jost, E., Barett, C., Rohe, I., Bokemeyer, C., Holyoake, T.L., and Brümmendorf, T.H.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: PLoS ONE
• Publisher: Public Library of Science
• ISSN: 1932-6203
• Copyright Holders: Copyright © 2011 Balabanov et al.
• First Published: First published in Public Library of Science 6 (4) : e19164
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher.

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