title: The MEK1/2 inhibitor, MEKi-1, induces cell death in chronic lymphocytic leukemia cells under conditions that mimic the tumor microenvironment and is synergistic with fludarabine.
abstract: 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.
authors: a Northern Blood Research Centre, Kolling Institute of Medical Research, Royal North Shore Hospital , St Leonards, Sydney , NSW , Australia.|b CLL Australian Research Consortium (CLLARC) , Sydney , NSW , Australia.
authors: Kyle
authors: K
authors: Crassini
authors: a Northern Blood Research Centre, Kolling Institute of Medical Research, Royal North Shore Hospital , St Leonards, Sydney , NSW , Australia.|b CLL Australian Research Consortium (CLLARC) , Sydney , NSW , Australia.
authors: William S
authors: WS
authors: Stevenson
authors: a Northern Blood Research Centre, Kolling Institute of Medical Research, Royal North Shore Hospital , St Leonards, Sydney , NSW , Australia.|b CLL Australian Research Consortium (CLLARC) , Sydney , NSW , Australia.
authors: Stephen P
authors: SP
authors: Mulligan
authors: a Northern Blood Research Centre, Kolling Institute of Medical Research, Royal North Shore Hospital , St Leonards, Sydney , NSW , Australia.|b CLL Australian Research Consortium (CLLARC) , Sydney , NSW , Australia.
authors: O Giles
authors: OG
authors: Best
mesh_terms: D000181:Acrylonitrile / Q000031:analogs & derivatives* / Q000494:pharmacology; D000814:Aniline Compounds / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015870:Gene Expression; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects*; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C000610759:MEK inhibitor I; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D051057:Proto-Oncogene Proteins c-akt; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D014740:Vidarabine; D000181:Acrylonitrile; C024352:fludarabine
keywords: Chronic lymphocytic leukemia; drug resistance; novel therapies