PUBLICATION
Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes
- Authors
- Herrero, A., Pinto, A., Colón-Bolea, P., Casar, B., Jones, M., Agudo-Ibáñez, L., Vidal, R., Tenbaum, S.P., Nuciforo, P., Valdizán, E.M., Horvath, Z., Orfi, L., Pineda-Lucena, A., Bony, E., Keri, G., Rivas, G., Pazos, A., Gozalbes, R., Palmer, H.G., Hurlstone, A., Crespo, P.
- ID
- ZDB-PUB-170214-137
- Date
- 2015
- Source
- Cancer Cell 28: 170-82 (Journal)
- Registered Authors
- Hurlstone, Adam
- Keywords
- none
- MeSH Terms
-
- Animals
- Carcinogenesis/drug effects*
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Chick Embryo
- Female
- HEK293 Cells
- Humans
- Immunoblotting
- Indoles/chemistry
- Indoles/metabolism
- Indoles/pharmacology
- Mice, Inbred C57BL
- Mice, Inbred NOD
- Mice, Nude
- Mice, SCID
- Mitogen-Activated Protein Kinase 1/antagonists & inhibitors*
- Mitogen-Activated Protein Kinase 1/chemistry
- Mitogen-Activated Protein Kinase 1/metabolism
- Models, Molecular
- Molecular Structure
- Protein Binding/drug effects
- Protein Kinase Inhibitors/chemistry
- Protein Kinase Inhibitors/metabolism
- Protein Kinase Inhibitors/pharmacology
- Protein Multimerization/drug effects*
- Protein Structure, Tertiary
- Signal Transduction/drug effects*
- Small Molecule Libraries/chemistry
- Small Molecule Libraries/metabolism
- Small Molecule Libraries/pharmacology*
- Xenograft Model Antitumor Assays/methods
- Zebrafish
- ras Proteins/metabolism*
- PubMed
- 26267534 Full text @ Cancer Cell
Citation
Herrero, A., Pinto, A., Colón-Bolea, P., Casar, B., Jones, M., Agudo-Ibáñez, L., Vidal, R., Tenbaum, S.P., Nuciforo, P., Valdizán, E.M., Horvath, Z., Orfi, L., Pineda-Lucena, A., Bony, E., Keri, G., Rivas, G., Pazos, A., Gozalbes, R., Palmer, H.G., Hurlstone, A., Crespo, P. (2015) Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes. Cancer Cell. 28:170-82.
Abstract
Nearly 50% of human malignancies exhibit unregulated RAS-ERK signaling; inhibiting it is a valid strategy for antineoplastic intervention. Upon activation, ERK dimerize, which is essential for ERK extranuclear, but not for nuclear, signaling. Here, we describe a small molecule inhibitor for ERK dimerization that, without affecting ERK phosphorylation, forestalls tumorigenesis driven by RAS-ERK pathway oncogenes. This compound is unaffected by resistance mechanisms that hamper classical RAS-ERK pathway inhibitors. Thus, ERK dimerization inhibitors provide the proof of principle for two understudied concepts in cancer therapy: (1) the blockade of sub-localization-specific sub-signals, rather than total signals, as a means of impeding oncogenic RAS-ERK signaling and (2) targeting regulatory protein-protein interactions, rather than catalytic activities, as an approach for producing effective antitumor agents.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping