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The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells
F Pellicano1, P Simara, A Sinclair
1Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
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.
Insights
The farnesyl transferase inhibitor BMS-214662 induces apoptosis in chronic myeloid leukemia (CML) stem cells. Combining it with a MEK inhibitor, PD184352, enhances this effect by targeting the ERK pathway.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Chronic myeloid leukemia (CML) stem/progenitor cells are resistant to tyrosine kinase inhibitors.
- Farnesyl transferase inhibitor BMS-214662 induces mitochondrial apoptosis in CML stem cells.
- The extracellular signal-regulated kinase (ERK) pathway is implicated in CML pathogenesis.
Purpose of the Study:
- To enhance the apoptotic effect of BMS-214662 in CML stem/progenitor cells.
- To investigate the combination therapy of BMS-214662 and a MEK inhibitor (PD184352).
- To target the ERK pathway in CML stem/progenitor cells.
Main Methods:
- Treatment of CD34+ CML stem/progenitor cells with BMS-214662 and PD184352.
- Assessment of apoptosis using Annexin-V staining and caspase activation assays.
- Analysis of ERK phosphorylation and BCL-2 family protein MCL-1 levels.
- Inhibition of K-RAS function using a dominant-negative mutant.
Main Results:
- Combination treatment potentiated BMS-214662-induced apoptosis in K562 cells and primary CML cells.
- Inhibition of ERK phosphorylation and increased caspase activation (caspase-3, -8, -9) were observed.
- Combination therapy led to potentiated mitochondrial damage and decreased MCL-1 levels.
- Inhibition of K-RAS function enhanced CML cell death, further augmented by combination treatment.
Conclusions:
- MEK inhibitor PD184352 enhances the selective targeting of CML stem/progenitor cells by BMS-214662.
- This combination therapy offers a potential strategy against CML stem cells responsible for disease persistence and relapse.
- Targeting the ERK pathway alongside farnesyl transferase inhibition may overcome resistance mechanisms in CML.