Blockade of MEK/ERK signaling enhances sunitinib-induced growth inhibition and apoptosis of leukemia cells possessing activating mutations of the FLT3 gene.

Abstract

The FMS-like tyrosine kinase 3 (FLT3) is a cell surface receptor tyrosine kinase. Activating mutations of this gene occur in nearly 30% of acute myelogenous leukemia (AML) patients. These mutations, in part, result in activation of mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways. In this study, we found that AZD6244 (ARRY-142886), a novel inhibitor of MEK1/2 kinases, effectively inhibited the proliferation of acute biphenotypic leukemia MV4-11 and acute monocytic leukemia MOLM13 cells. The concentrations that inhibited 50% growth were approximately 0.3 and 1.2 microM, respectively, as measured by thymidine uptake on day 2 of culture. AZD6244 potently down-regulated the levels of phospho-ERK1/2 and its downstream effector, p-p70S6K, in the MV4-11 and MOLM13 cells as measured by Western blot analysis. Interestingly, when AZD6244 was combined with sunitinib, a FLT3 kinase inhibitor, growth inhibition and apoptosis of both MV4-11 and MOLM13 cells were synergistically enhanced in association with further down-regulation of phospho-ERK1/2 and p-p70S6K in these cells. Taken together, concomitant blockade of FLT3 and MEK signaling represents a promising treatment strategy for individuals with leukemia who possess activating mutations of FLT3.

• Authors: Chie Nishioka, Takayuki Ikezoe, Jing Yang, Ayako Takeshita, Ayuko Taniguchi, Naoki Komatsu, Kazuto Togitani, H Phillip Koeffler, Akihito Yokoyama
• Journal: Leukemia research (Leuk Res) Vol. 32 Issue 6 Pg. 865-72 (Jun 2008) ISSN: 0145-2126 [Print] England
• PMID: 17983653 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• AZD 6244
• Benzimidazoles
• Indoles
• Pyrroles
• FLT3 protein, human
• fms-Like Tyrosine Kinase 3
• Ribosomal Protein S6 Kinases, 70-kDa
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• MAP Kinase Kinase 1
• MAP2K1 protein, human
• Sunitinib

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols
• Apoptosis (drug effects, physiology)
• Benzimidazoles (therapeutic use)
• Cell Proliferation (drug effects)
• Female
• Humans
• Indoles (therapeutic use)
• Leukemia (drug therapy, genetics, pathology)
• Leukemia, Megakaryoblastic, Acute (drug therapy, genetics, pathology)
• Leukemia, Myeloid, Acute (drug therapy, genetics, pathology)
• MAP Kinase Kinase 1 (antagonists & inhibitors, metabolism)
• Male
• Middle Aged
• Mitogen-Activated Protein Kinase 1 (antagonists & inhibitors, metabolism)
• Mitogen-Activated Protein Kinase 3 (antagonists & inhibitors, metabolism)
• Mutation (genetics)
• Pyrroles (therapeutic use)
• Ribosomal Protein S6 Kinases, 70-kDa (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Sunitinib
• Tumor Cells, Cultured
• fms-Like Tyrosine Kinase 3 (genetics)