Journal article
Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic
MS Cragg, ES Jansen, M Cook, C Harris, A Strasser, CL Scott
Journal of Clinical Investigation | AMER SOC CLINICAL INVESTIGATION INC | Published : 2008
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 inhibit..
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Awarded by National Cancer Institute
Funding Acknowledgements
We are grateful to G. Boyle, P. Hersey, and J. Blaydes for the kind gift of cell lines, J. Baell for ABT-737, and R. Anderson for antibodits. We thank all of our colleagues in the Molecular Genetics of Cancer Division and Cancer Sciences Division of Southampton University for gifts of reagents, scientific advice, and technical support. This work was supported by the National Health and Medical Research Council (NHMRC; program no. 257502; RD Wright Biomedical CDA 40667S), by a grant from the Leukemia and Lymphoma Society (SCOR grant no. 7015), by National Cancer Institure, NIH, grants CA 80188 and CA 43540, and by a Leukemia Research UK fellowship (to M.S. Cragg).