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Chronic Myeloproliferative Neoplasias

The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells

Leukemia volume 25, pages 1159–1167 (2011)Cite this article

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Abstract

The cytotoxic farnesyl transferase inhibitor BMS-214662 has been shown to potently induce mitochondrial apoptosis in primitive CD34+ chronic myeloid leukaemia (CML) stem/progenitor cells. Here, to enhance the BMS-214662 apoptotic effect, we further targeted the extracellular signal-regulated kinase (ERK) pathway, downstream of BCR–ABL, by treating CD34+ CML stem/progenitor cells with a highly selective adenosine triphosphate (ATP) non-competitive MEK inhibitor, PD184352. PD184352 increased the apoptotic effect of BMS-214662 in a CML blast crisis cell line, K562, and in primary chronic phase CD34+ CML cells. Compared with BMS-214662, after combination treatment we observed inhibition of ERK phosphorylation, increased Annexin-V levels, caspase-3, -8 and -9 activation and potentiated mitochondrial damage, associated with decreased levels of anti-apoptotic BCL-2 family protein MCL-1. Inhibition of K-RAS function by a dominant-negative mutant resulted in CML cell death and this process was further enhanced by the addition of BMS-214662 and PD184352. Together, these findings suggest that the addition of a MEK inhibitor improves the ability of BMS-214662 to selectively target CML stem/progenitor cells, notoriously insensitive to tyrosine kinase inhibitor treatment and presumed to be responsible for the persistence and relapse of the disease.

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Acknowledgements

We thank Dr R Weinmann and Dr F Lee (Bristol–Myers Squibb) for providing BMS-214662 and BMS-225975, Professor C Marshall for the DN-MEK1 plasmid and Dr D Matallanas-Gomez for the K-RAS N17 plasmid. FP received funding from Bristol–Myers Squibb, the Rockefeller Foundation, Chief Scientific Office and Glasgow Royal Infirmary Endowments. PS received funding from the Ministry of Education of Czech Republic MSM-0021622430 and NPVII (2B06052). GVH and AS received funding from Biotechnology and Biological Sciences Research Council and Medical Research Council. MC received funding from Scottish Funding Council (SCD/04) and Chief Scientist's Office for Scotland Leukaemia Research Trust for Scotland. SG received funding from the NCI (CA 100866-01, CA93738-05) and the Leukemia and Lymphoma Society of America (LSA-6181-10). We would like to thank all UK CML patients and normal donors, haematologists and non-medical staff who have contributed to our biobank.

Author Contributions

FP designed the research. FP, PS, AS and GVH performed the experiments and analyzed the data. TLH and MC provided suggestions in experimental design. FP, PS and TLH co-wrote the paper. TLH supervised the project. SG provided PD184352. All authors commented on the paper.

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  1. F Pellicano and P Šimara: Joint first author.

Authors and Affiliations

  1. Paul O’Gorman Leukaemia Research Centre, College of Medical, Veterinary and Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK

    F Pellicano, A Sinclair, G V Helgason, M Copland & T L Holyoake

  2. Centre for Biomedical Image Analysis, Faculty of Informatics, Masaryk University, Brno, Czech Republic

    P Šimara

  3. Departments of Medicine, Biochemistry, and Pharmacology, Virginia Commonwealth University/Massey Cancer Center, Richmond, VA, USA

    S Grant

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  1. F Pellicano
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Correspondence to T L Holyoake.

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Competing interests

TLH receives per year approximately $10 000 combined from consultancy, speaking fees, honoraria and service on advisory boards from Bristol–Myers Squibb and Novartis. TLH also received research funding from Bristol-Myers Squibb. MC has undertaken consultancy work for Bristol–Myers Squibb and is on its Advisory Board and has received honoraria from both Bristol–Myers Squibb and Novartis within the last 2 years. The remaining authors declare no conflict of interest.

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Pellicano, F., Šimara, P., Sinclair, A. et al. The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells. Leukemia 25, 1159–1167 (2011). https://doi.org/10.1038/leu.2011.67

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