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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
An investigation of the MEK/ERK inhibitor U0126 in acute myeloid leukemia
A H J Kerr1, J A James, M A Smith
1Centre for Research in Biomedicine, Faculty of Applied Sciences, University of the West of England, Bristol BS16 1QY, UK. Alastair.Kerr@uwe.ac.uk
Abstract:
Blockade of mitogen-activated protein kinase kinase (MEK1/2), part of the extracellular signal-regulated kinase (ERK) or p44/42 mitogen-activated protein kinase (MAPK) pathway, has been shown in some instances to cause apoptosis in leukemic blast cells. This investigation examined the effect of the potent MEK/ERK inhibitor U0126 on apoptosis in acute myeloblastic leukemia (AML) cell lines, and acute leukemic and non-leukemic patient samples. The pro-apoptotic effect of the inhibitor varied across the five cell lines tested (KG1a, HEL, TF-1, MO7e, and THP-1) from highly significant induction of apoptosis to no apparent response. The pro-apoptotic effect of U0126 in the most sensitive cell line, KG1a, appeared to be related to its CD34 positivity. Three of five leukemic bone marrow samples showed considerable sensitivity to the inhibitor and a similar association with CD34 expression was evident. Interestingly, control marrow cells from six non-leukemic patients did not show a significant effect when exposed to U0126. These results suggest that this agent may offer a potential alternative to standard chemotherapy with a particular role in the most primitive types of leukemia, these often being the most resistant to standard chemotherapy.
Insights
The MEK/ERK inhibitor U0126 induces apoptosis in some acute myeloblastic leukemia (AML) cells, particularly CD34-positive cells. This suggests potential for treating primitive, chemotherapy-resistant leukemias.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- The mitogen-activated protein kinase kinase (MEK1/2) pathway, including extracellular signal-regulated kinase (ERK), plays a role in cell survival.
- Dysregulation of the MEK/ERK pathway is implicated in various cancers, including leukemia.
- Targeting MEK/ERK signaling is a potential therapeutic strategy for hematological malignancies.
Purpose of the Study:
- To investigate the efficacy of the MEK/ERK inhibitor U0126 in inducing apoptosis in acute myeloblastic leukemia (AML) cell lines and patient samples.
- To determine if sensitivity to U0126 correlates with specific cellular markers like CD34.
- To evaluate the potential of U0126 as a targeted therapy for leukemia, especially for primitive and resistant subtypes.
Main Methods:
- Treatment of five AML cell lines (KG1a, HEL, TF-1, MO7e, THP-1) with the MEK/ERK inhibitor U0126.
- Assessment of apoptosis induction in cell lines and primary patient samples (leukemic and non-leukemic bone marrow).
- Correlation analysis between U0126 sensitivity, CD34 expression, and patient sample type.
Main Results:
- U0126 demonstrated variable pro-apoptotic effects across AML cell lines, ranging from significant induction to no response.
- The most sensitive cell line, KG1a, showed increased apoptosis, potentially linked to CD34 positivity.
- Three out of five acute leukemic bone marrow samples exhibited sensitivity to U0126, also associated with CD34 expression.
- Non-leukemic control bone marrow cells showed no significant response to U0126 treatment.
Conclusions:
- MEK/ERK inhibition with U0126 can induce apoptosis in a subset of AML cells.
- CD34 expression may predict sensitivity to U0126, suggesting a role in targeting primitive leukemic cells.
- U0126 represents a potential therapeutic agent for AML, particularly for primitive and chemotherapy-resistant leukemia subtypes.
