• Open Access

The novel Aurora A kinase inhibitor MLN8237 is active in resistant chronic myeloid leukaemia and significantly increases the efficacy of nilotinib

Authors

  • Kevin R. Kelly,

    1. Department of Medicine, Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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  • Jeffrey Ecsedy,

    1. Millennium Pharmaceuticals, Cambridge, MA, USA
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  • Ernest Medina,

    1. Department of Medicine, Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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  • Devalingam Mahalingam,

    1. Department of Medicine, Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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  • Swaminathan Padmanabhan,

    1. Department of Medicine, Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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  • Steffan T. Nawrocki,

    1. Department of Medicine, Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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  • Francis J. Giles,

    1. Department of Medicine, Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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  • Jennifer S. Carew

    Corresponding author
    1. Department of Medicine, Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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Jennifer S. CAREW, The Institute for Drug Development, CTRC at UT Health Science Center, 14960 Omicron Drive, San Antonio, TX 78245, USA.
Tel.: +1-210-450-3895
Fax: +1-210-450-8411
E-mail: carew@uthscsa.edu

Abstract

Novel therapies are urgently needed to prevent and treat tyrosine kinase inhibitor resistance in chronic myeloid leukaemia (CML). MLN8237 is a novel Aurora A kinase inhibitor under investigation in multiple phase I and II studies. Here we report that MLN8237 possessed equipotent activity against Ba/F3 cells and primary CML cells expressing unmutated and mutated forms of breakpoint cluster region-Abelson kinase (BCR-ABL). Notably, this agent retained high activity against the T315I and E255K BCR-ABL mutations, which confer the greatest degree of resistance to standard therapy. MLN8237 treatment disrupted cell cycle kinetics, induced apoptosis, caused a dose-dependent reduction in the expression of the large inhibitor of apoptosis protein Apollon, and produced a morphological phenotype consistent with Aurora A kinase inhibition. In contrast to other Aurora kinase inhibitors, MLN8237 did not significantly affect BCR-ABL activity. Moreover, inhibition of Aurora A with MLN8237 significantly increased the in vitro and in vivo efficacy of nilotinib. Targeted knockdown of Apollon sensitized CML cells to nilotinib-induced apoptosis, indicating that this is an important factor underlying MLN8237’s ability to increase the efficacy of nilotinib. Our collective data demonstrate that this combination strategy represents a novel therapeutic approach for refractory CML that has the potential to suppress the emergence of T315I mutated CML clones.

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