Omacetaxine mepesuccinate prevents cytokine-dependent resistance to nilotinib in vitro: potential role of the common β-subunit c of cytokine receptors
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...
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| Main Authors: | , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
13 January 2012
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| In: |
Leukemia
Year: 2012, Volume: 26, Issue: 6, Pages: 1321-1328 |
| ISSN: | 1476-5551 |
| DOI: | 10.1038/leu.2011.380 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1038/leu.2011.380 Verlag, Volltext: https://www.nature.com/articles/leu2011380 
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| Author Notes: | T. Klag, N. Härtel, P. Erben, J. Schwaab, U. Schnetzke, T. Schenk, A. Hochhaus, P. La Rosée |
| Summary: | 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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| Item Description: | Gesehen am 04.02.2019 |
| Physical Description: | Online Resource |
| ISSN: | 1476-5551 |
| DOI: | 10.1038/leu.2011.380 |