MEK Inhibition Enhances ABT-737-Induced Leukemia Cell Apoptosis via Prevention of ERK activated MCL-1 induction and Modulation of MCL-1/BIM Complex

摘要

Recently, strategies for AML therapy have been developed that target anti-apoptotic BCL2 family members using BH3 mimetic drugs such as ABT-737. Though effective against BCL2 and BCL-XL, ABT-737 poorly inhibits MCL-1. Here we report that, unexpectedly, ABT-737 induces activation of ERK and induction of MCL-1 in AML cells. MEK inhibitors such as PD0325901 and CI-1040 have been used successfully to suppress MCL-1. We report that PD0325901 blocked ABT-737 –induced MCL-1 expression and when combined with ABT-737 resulted in potent synergistic killing of AML derived cell lines, primary AML blast and CD34+38−123+ progenitor/stem cells. Finally, we tested the combination of ABT-737 and CI-1040 in a murine xenograft model using MOLM-13 human leukemia cells. While control and CI-1040 treated mice exhibited progressive leukemia growth, ABT-737 and, to a significantly greater extent, ABT-737 + CI-1040 exerted major anti-leukemia activity. Collectively, results demonstrate unexpected anti-apoptotic interaction between the BCL2 family-targeted BH3 mimetic ABT-737 and MAPK signaling in AML cells: the BH3 mimetic is not only restrained in its activity by MCL-1, but also induces it’s expression. However, concomitant inhibition by BH3 mimetics and MEK inhibitors could abrogate this effect and may be developed into a novel and effective therapeutic strategy for patients with AML.