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1.
FEBS J ; 276(21): 6050-62, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19788418

ABSTRACT

The BCL-2 homology domain 3 (BH3)-only protein, B-cell lymphoma 2 interacting mediator of cell death (BIM) is a potent pro-apoptotic protein belonging to the B-cell lymphoma 2 protein family. In recent years, advances in basic biology have provided a clearer picture of how BIM kills cells and how BIM expression and activity are repressed by growth factor signalling pathways, especially the extracellular signal-regulated kinase 1/2 and protein kinase B pathways. In tumour cells these oncogene-regulated pathways are used to counter the effects of BIM, thereby promoting tumour cell survival. In parallel, a new generation of targeted therapeutics has been developed, which show remarkable specificity and efficacy in tumour cells that are addicted to particular oncogenes. It is now apparent that the expression and activation of BIM is a common response to these new therapeutics. Indeed, BIM has emerged from this marriage of basic and applied biology as an important mediator of tumour cell death in response to such drugs. The induction of BIM alone may not be sufficient for significant tumour cell death, as BIM is more likely to act in concert with other BH3-only proteins, or other death pathways, when new targeted therapeutics are used in combination with traditional chemotherapy agents. Here we discuss recent advances in understanding BIM regulation and review the role of BIM as a mediator of tumour cell death in response to novel oncogene-targeted therapeutics.


Subject(s)
Apoptosis Regulatory Proteins/physiology , Apoptosis , Autophagy , Membrane Proteins/physiology , Neoplasms/drug therapy , Oncogenes , Proto-Oncogene Proteins/physiology , Animals , Bcl-2-Like Protein 11 , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Cell Survival , ErbB Receptors/genetics , Extracellular Signal-Regulated MAP Kinases/metabolism , Fusion Proteins, bcr-abl/antagonists & inhibitors , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Mutation , Neoplasms/pathology , Protein Processing, Post-Translational , Proto-Oncogene Proteins B-raf/genetics , Signal Transduction
2.
Int J Cancer ; 125(10): 2332-41, 2009 Nov 15.
Article in English | MEDLINE | ID: mdl-19637312

ABSTRACT

Mutations in KRAS or BRAF frequently manifest in constitutive activation of the MEK1/2-ERK1/2 signalling pathway. The MEK1/2-selective inhibitor, AZD6244 (ARRY-142886), blocks ERK1/2 activation and is currently undergoing clinical evaluation. Tumour cells can vary markedly in their response to MAPK or ERK kinase (MEK) inhibitors, and the presence of a BRAF mutation is thought to predict sensitivity, with the RAS mutations being associated with intrinsic resistance. We analysed cell proliferation in a panel of 19 colorectal cancer cell lines and found no simple correlation between BRAF or KRAS mutation and sensitivity to AZD6244, though cells that harbour neither mutation tended to be resistant. Cells that were sensitive arrested in G(1) and/or underwent apoptosis and the presence of BRAF or KRAS mutation was not sufficient to predict either fate. Cell lines that were resistant to AZD6244 exhibited low or no ERK1/2 activation or exhibited coincident activation of ERK1/2 and protein kinase B (PKB), the latter indicative of activation of the PI3K pathway. In cell lines with coincident ERK1/2 and PKB activation, sensitivity to AZD6244 could be re-imposed by any of the 3 distinct PI3K/mTOR inhibitors. We conclude that AZD6244 is effective in colorectal cancer cell lines with BRAF or KRAS mutations. Sensitivity to MEK1/2 inhibition correlates with a biochemical signature; those cells with high ERK1/2 activity (whether mutant for BRAF or KRAS) evolve a dependency upon that pathway and tend to be sensitive to AZD6244 but this can be offset by high PI3K-dependent signalling. This may have implications for the use of MEK inhibitors in combination with PI3K inhibitors.


Subject(s)
Benzimidazoles/pharmacology , Colorectal Neoplasms/metabolism , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 2/antagonists & inhibitors , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Animals , Apoptosis , Blotting, Western , Cell Line, Tumor , Cell Proliferation , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Drug Resistance, Neoplasm , Flow Cytometry , Humans , MAP Kinase Kinase 1/metabolism , MAP Kinase Kinase 2/metabolism , Male , Mice , Mice, Inbred BALB C , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Mutation/genetics , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras) , RNA, Small Interfering/pharmacology , ras Proteins/genetics
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