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Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic
Mark S. Cragg, … , Andreas Strasser, Clare L. Scott
Mark S. Cragg, … , Andreas Strasser, Clare L. Scott
Published October 23, 2008
Citation Information: J Clin Invest. 2008;118(11):3651-3659. https://doi.org/10.1172/JCI35437.
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Research Article

Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic

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Abstract

B-RAF is frequently mutated in solid tumors, resulting in activation of the MEK/ERK signaling pathway and ultimately tumor cell growth and survival. MEK inhibition in these cells results in cell cycle arrest and cytostasis. Here, we have shown that MEK inhibition also triggers limited apoptosis of human tumor cell lines with B-RAF mutations and that this effect was dependent on upregulation and dephosphorylation of the proapoptotic, Bcl-2 homology 3–only (BH3-only) Bcl-2 family member Bim. However, upregulation of Bim was insufficient for extensive apoptosis and was countered by overexpression of Bcl-2. To overcome apoptotic resistance, we treated the B-RAF mutant cells both with MEK inhibitors and with the BH3 mimetic ABT-737, resulting in profound synergism and extensive tumor cell death. This treatment was successful because of both efficient antagonism of the prosurvival Bcl-2 family member Mcl-1 by Bim and inhibition of Bcl-2 and Bcl-xL by ABT-737. Critically, addition of ABT-737 converted the predominantly cytostatic effect of MEK inhibition to a cytotoxic effect, causing long-term tumor regression in mice xenografted with human tumor cell lines. Thus, the therapeutic efficacy of MEK inhibition requires concurrent unleashing of apoptosis by a BH3 mimetic and represents a potent combination treatment for tumors harboring B-RAF mutations.

Authors

Mark S. Cragg, Elisa S. Jansen, Michele Cook, Claire Harris, Andreas Strasser, Clare L. Scott

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Figure 4

MEK inhibition causes induction and dephosphorylation of Bim in a range of B-RAF mutant tumor cells.

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MEK inhibition causes induction and dephosphorylation of Bim in a range ...
(A) MM200-1, SkMel-28, Mel-RMU, and MCF-7 tumor-derived cell lines were not treated, were treated with 20 μM UO126 for the indicated time points, or were treated with the indicated concentrations of UO126 for 18 h, and were assessed for levels of Bim, phosphorylated ERK1/2, and total ERK1/2 by Western blotting. D, DMSO control. (B) SkMel-28 cells were not treated or were treated for 18 h with 20 μM UO126, harvested, and lysed. Lysates were not treated or were treated with λ phosphatase and then assessed by Western blotting for the migration of Bim on SDS-PAGE. Arrow indicates the faint diffuse band of Bim present in untreated healthy cells. (C) Untreated PC3, MM200-1, SkMel-28, Mel-RMU, and Colo205 cells were assessed by Western blotting for the indicated apoptosis-related proteins, all on the same membranes to allow direct comparisons.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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