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

doi:10.3109/10428194.2015.1032963

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

Leuk Lymphoma. 2015;56(12):3407-17. doi: 10.3109/10428194.2015.1032963. Epub 2015 Aug 26.

Authors

Kyle Crassini^{1

2}, William S Stevenson^{1

2}, Stephen P Mulligan^{1

2}, O Giles Best^{1

2}

Affiliations

¹ a Northern Blood Research Centre, Kolling Institute of Medical Research, Royal North Shore Hospital , St Leonards, Sydney , NSW , Australia.
² b CLL Australian Research Consortium (CLLARC) , Sydney , NSW , Australia.

PMID: 25804768
DOI: 10.3109/10428194.2015.1032963

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.

Keywords: Chronic lymphocytic leukemia; drug resistance; novel therapies.

MeSH terms

Acrylonitrile / analogs & derivatives*
Acrylonitrile / 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
Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
Leukemia, Lymphocytic, Chronic, B-Cell / 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
Myeloid Cell Leukemia Sequence 1 Protein / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Stromal Cells / drug effects
Stromal Cells / metabolism
Tumor Microenvironment / drug effects*
Vidarabine / analogs & derivatives*
Vidarabine / pharmacology

Substances

Aniline Compounds
Antineoplastic Agents
MEK inhibitor I
Myeloid Cell Leukemia Sequence 1 Protein
Proto-Oncogene Proteins c-akt
MAP Kinase Kinase 1
MAP Kinase Kinase 2
MAP2K1 protein, human
Vidarabine
Acrylonitrile
fludarabine