mk-2206 and binimetinib

Several key pathways mediate signaling via the B-cell receptor, including the mitogen-activated protein kinase-ERK1/2 pathway. However, inhibition of MEK1/2, a key component of the MAPK-ERK1/2 signaling cascade, results in paradoxical activation of AKT in chronic lymphocytic leukemia (CLL) cells. In the current study we demonstrate synergy between the MEK1/2 inhibitor binimetinib and the AKT inhibitor MK2206, which combined induce apoptosis of primary CLL cells and restrict the cell cycle progression and proliferation of the OSU-CLL cell line. The mechanisms of action of the drug combination involve dual inhibition of MAPK-ERK1/2 and AKT signaling and down-regulation of Mcl-1 expression. Collectively, these data suggest that dual inhibition of MEK1/2 and AKT may represent a therapeutic option for CLL, capable of overcoming the pro-survival effects of the lymph node and bone marrow microenvironments.

Topics: Apoptosis; Benzimidazoles; Coculture Techniques; Drug Therapy, Combination; Heterocyclic Compounds, 3-Ring; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Proto-Oncogene Proteins c-akt; Signal Transduction; Tumor Cells, Cultured; Tumor Microenvironment