The Raf-1/MEK/ERK1/2 pathway has become a focus for novel cancer therapies. This study sought to investigate whether targeting MEK1/2 may represent a therapeutic option for chronic lymphocytic leukemia (CLL). The MEK1/2 inhibitor, MEKi-1, induced apoptosis of CLL cells and was synergistic with fludarabine under conditions that mimic the tumor microenvironment, irrespective of poor-risk characteristics. MEKi-1 down-regulated the activities of AKT and ERK1/2 and was synergistic with fludarabine through a mechanism that involved potentiation of DNA damage and attenuation of the activity of ERK1/2 and expression of Mcl-1. This study highlights the significant role of the mitogen-activated protein kinase (MAPK)-ERK1/2 pathway in mediating the effects of the CLL tumor microenvironment and suggests that targeting MEK1/2 in CLL cells may impact upon the activity of both ERK1/2 and AKT. Inhibitors of MEK1/2 as single agents or in combination with DNA-damaging agents may represent a novel therapeutic strategy for CLL.
- Acrylonitrile/*analogs & derivatives/pharmacology Aniline Compounds/*pharmacology Antineoplastic Agents/*pharmacology Apoptosis/drug effects Cell Death/drug effects Cell Line, Tumor Coculture Techniques DNA Damage/drug effects Dose-Response Relationship, Drug Drug Synergism Gene Expression Humans Leukemia, Lymphocytic, Chronic, B-Cell/genetics/*metabolism/pathology MAP Kinase Kinase 1/*antagonists & inhibitors MAP Kinase Kinase 2/*antagonists & inhibitors MAP Kinase Signaling System/drug effects Myeloid Cell Leukemia Sequence 1 Protein/genetics/metabolism Proto-Oncogene Proteins c-akt/metabolism Stromal Cells/drug effects/metabolism Tumor Microenvironment/*drug effects Vidarabine/*analogs & derivatives/pharmacology Chronic lymphocytic leukemia drug resistance novel therapies
- Chronic lymphocytic leukemia
- drug resistance
- novel therapies