Omacetaxine mepesuccinate prevents cytokine-dependent resistance to nilotinib in vitro

• Verfasst von: Klag, Thomas-Matthias [VerfasserIn]
• Verfasst von: Härtel, Nicolai [VerfasserIn]
• Verfasst von: Erben, Philipp [VerfasserIn]
• Verfasst von: Schwaab, Juliana [VerfasserIn]
• Titel: Omacetaxine mepesuccinate prevents cytokine-dependent resistance to nilotinib in vitro
• Titelzusatz: potential role of the common β-subunit c of cytokine receptors
• Verf.angabe: T. Klag, N. Härtel, P. Erben, J. Schwaab, U. Schnetzke, T. Schenk, A. Hochhaus, P. La Rosée
• E-Jahr: 2012
• Jahr: 13 January 2012
• Umfang: 8 S.
• Fussnoten: Gesehen am 04.02.2019
• Titel Quelle: Enthalten in: Leukemia
• Ort Quelle: London : Springer Nature, 1997
• Jahr Quelle: 2012
• Band/Heft Quelle: 26(2012), 6, Seite 1321-1328
• ISSN Quelle: 1476-5551
• DOI: doi:10.1038/leu.2011.380
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1587207680

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.