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

Kyle Crassini, William S. Stevenson, Stephen P. Mulligan, O. Giles Best

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)3407-3417
Number of pages11
JournalLeukemia & lymphoma
Volume56
Issue number12
DOIs
Publication statusPublished - 2 Dec 2015
Externally publishedYes

Keywords

  • 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

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