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Sensitivity and Resistance to Therapy

Omacetaxine mepesuccinate prevents cytokine-dependent resistance to nilotinib in vitro: potential role of the common β-subunit c of cytokine receptors

Leukemia volume 26, pages 1321–1328 (2012)Cite this article

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Abstract

Overcoming resistance against BCR-ABL-inhibitors in chronic myeloid leukemia (CML) is central to prevent progression to advanced phase disease. Kinase mutations of BCR-ABL and cytokine-mediated modulation of response to tyrosine kinase inhibitors (TKIs) are key mechanisms governing clinical response to imatinib and second generation TKIs. Omacetaxine mepesuccinate is effective in imatinib-resistant CML with reported stem cell activity. We specifically thought to explore omacetaxine in the context of the pan-resistant mutant T315I, and in its potential to modify cytokine-dependent resistance. Omacetaxine was investigated in cell lines and primary CD34+ enriched progenitor cells from patients with CML. Addition of cytokines, shown to revert the efficacy of TKIs in BCR-ABL-positive cells, does not affect omacetaxine mediated antiproliferative activity, neither in cell lines nor in primary CML CD34+ progenitor cells. Looking at potential mechanisms, we found marked downregulation of the common β-subunit c of the cytokine-receptors (cCRβc) for IL3, IL5 and GM-CSF by omacetaxine in cell lines and primary progenitor cultures. The observed cytokine-independent in-vitro cytotoxicity of omacetaxine may be explained by downregulation of cCRβc. Whether this can be used clinically as a means to optimize the stem cell activity of TKIs merits further evaluation.

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Acknowledgements

We would like to thank Ms Susanne Brendel and Ms Silke Will for expert technical assistance. Chemgenex Pharmaceuticals (Menlo Park, CA, USA) provided Omacetaxine. AH received research support by Novartis Pharmaceuticals, Nürnberg, Germany and Chemgenex Pharmaceuticals. This work was funded by the Max Eder program, Deutsche Krebshilfe, Germany (PL).

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Authors and Affiliations

  1. Abteilung Hämatologie und internistische Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany

    T Klag, U Schnetzke, T Schenk, A Hochhaus & P La Rosée

  2. III. Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany

    N Härtel, P Erben & J Schwaab

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  1. T Klag
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Correspondence to P La Rosée.

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Competing interests

AH received research support by Novartis Pharmaceuticals, Nürnberg, Germany and Chemgenex Pharmaceuticals (Menlo Park, CA, USA). PL receives speaker honorarium from Novartis.

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Klag, T., Härtel, N., Erben, P. et al. Omacetaxine mepesuccinate prevents cytokine-dependent resistance to nilotinib in vitro: potential role of the common β-subunit c of cytokine receptors. Leukemia 26, 1321–1328 (2012). https://doi.org/10.1038/leu.2011.380

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