Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic.
Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic.
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.
3651-3659
Cragg, Mark S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Jansen, Elisa S.
62539592-d6db-4a70-8c33-dcd2e00da8f2
Cook, Michele
721eaefd-eb4e-4faa-bb98-c814fb7845d2
Harris, Claire
ce357569-f567-477d-88cb-79425d886400
Strasser, Andreas
c9774edf-fa89-481c-8cc4-21f403859700
Scott, Clare L.
9aee7a06-6161-4d3b-8721-c395654dca5f
3 November 2008
Cragg, Mark S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Jansen, Elisa S.
62539592-d6db-4a70-8c33-dcd2e00da8f2
Cook, Michele
721eaefd-eb4e-4faa-bb98-c814fb7845d2
Harris, Claire
ce357569-f567-477d-88cb-79425d886400
Strasser, Andreas
c9774edf-fa89-481c-8cc4-21f403859700
Scott, Clare L.
9aee7a06-6161-4d3b-8721-c395654dca5f
Cragg, Mark S., Jansen, Elisa S., Cook, Michele, Harris, Claire, Strasser, Andreas and Scott, Clare L.
(2008)
Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic.
Journal of Clinical Investigation, 118 (11), .
(doi:10.1172/JCI35437).
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.
This record has no associated files available for download.
More information
Published date: 3 November 2008
Organisations:
Cancer Sciences
Identifiers
Local EPrints ID: 73223
URI: http://eprints.soton.ac.uk/id/eprint/73223
ISSN: 0021-9738
PURE UUID: a3544b1c-4be5-492c-8ee7-2cb2c8367210
Catalogue record
Date deposited: 03 Mar 2010
Last modified: 14 Mar 2024 02:41
Export record
Altmetrics
Contributors
Author:
Elisa S. Jansen
Author:
Michele Cook
Author:
Claire Harris
Author:
Andreas Strasser
Author:
Clare L. Scott
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics