Dual inhibition of MEK1/2 and AKT by binimetinib and MK2206 induces apoptosis of chronic lymphocytic leukemia cells under conditions that mimic the tumor microenvironment

Yandong Shen, Kyle Crassini, Suneet Sandhu, Narjis Fatima, Richard I. Christopherson, Stephen P. Mulligan, O. Giles Best

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1632-1643
Number of pages12
JournalLeukemia and Lymphoma
Volume60
Issue number7
DOIs
Publication statusPublished - 2019
Externally publishedYes

Keywords

  • Chronic lymphocytic leukemia
  • therapy
  • tumor microenvironment

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