RETRACTED ARTICLE: MEK inhibition enhances ABT-737-induced leukemia cell apoptosis via prevention of ERK-activated MCL-1 induction and modulation of MCL-1/BIM complex

Abstract

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.

Bcl-2/Bcl-xL Inhibition Increases the Efficacy of MEK Inhibition Alone and in Combination with PI3 Kinase Inhibition in Lung and Pancreatic Tumor Models

“…Navitoclax did not alter ERK or p90RSK phosphorylation, and the effects of MEK inhibition on ERK and RSK phosphorylation as well as BIM stabilization are comparable following combination treatment compared with the single-agent G-963. At early time points, MCL1 levels increase in navitoclax treated cells and decrease in G-963-treated cells, and the effect is balanced out in the combination treatment setting, similar to an effect previously observed in AML models with ABT-737 and MEK inhibition (25). Overall, signaling downstream of MEK does not seem to be impacted by navitoclax, but there is enhanced PARP cleavage in all cell lines treated with the combination compared with either single-agent (Fig.…”

“…Cragg and colleagues showed BIM-dependent combination efficacy of a MEK inhibitor and ABT-737, a compound with similar biochemical activity to navitoclax, in several BRAF mutant models (12). Konopleva and colleagues showed similar combination efficacy in AML models (25). In this work, we set out to determine the effectiveness of a navitoclax/MEK inhibitor combination in a large panel of non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma derived cell lines with the aim of (1) determining the prevalence of MEK inhibitor/navitoclax synergy in cancer lines that frequently harbor activating KRAS mutations, (2) identifying predictive biomarkers for the combination in these cancers, and (3) evaluating combination mechanism of action.…”

Cooperation of IRAK1/4 inhibitor and ABT-737 in nanoparticles for synergistic therapy of T cell acute lymphoblastic leukemia

“…ABT-737, an agent that disrupts microtubules, has the best synergistic effect with IRAK1/4 inhibitor in killing T-ALL cells due to the combination of BCL2 and BCL-xL impairment by ABT-737 and the dramatic decrease of MCL1 levels by IRAK1/4 inhibitor. 7,[10][11][12] Despite the improvement in cytotoxic effect on malignant T-ALL cells by the combination of the IRAK1/4 inhibitor and ABT-737, a nanoparticle based drug delivery system has been proven to increase the effect of chemotherapy drugs through enhancing permeability and retention in tumor cells, improving pharmacokinetic profiles, and reducing side effects. [13][14][15][16][17][18] Therefore, here we co-encapsulated IRAK1/4 inhibitor and ABT-737 into biodegradable and biocompatible polyethylene glycol (PEG) modified poly (lactic-co-glycolic acid) (PEG-PLGA) polymer nanoparticles (IRAK/ABT-NP) as a novel and advanced therapy strategy for T-ALL treatment.…”

Increase of Drug Resistance of Acute Myeloid Leukemia Cells in Multicellular Aggregates in Vitro

“…На сегодняшний день известны внутриклеточные протеинкиназы и транскрипционные факторы, ко-торые принимают участие в механизме лекарствен-ной устойчивости лейкозных клеток, к ним относят следующие сигнальные белки: mTOR, PI3K, ABL1, FLT3, JAK2, митоген-активируемые протеинкиназы (MAPK) и фактор, индуцируемый гипоксией (HIF-1) [6,7,8,9,10,11,12]. Все эти сигнальные белки так-же могут участвовать в механизмах de novo лекар-ственной устойчивости клеток ОМЛ.…”