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- PMID: 26267534
- UKPMCID: 26267534
- DOI: 10.1016/j.ccell.2015.07.001
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Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes.
Herrero, Ana; Pinto, Adán; Colón-Bolea, Paula; Casar, Berta; Jones, Mary; Agudo-Ibáñez, Lorena; Vidal, Rebeca; Tenbaum, Stephan P; Nuciforo, Paolo; Valdizán, Elsa M; Horvath, Zoltan; Orfi, Laszlo; Pineda-Lucena, Antonio; Bony, Emilie; Keri, Gyorgy; Rivas, Germán; Pazos, Angel; Gozalbes, Rafael; Palmer, Héctor G; Hurlstone, Adam; Crespo, Piero
Cancer cell. 2015;28(2):170-82.
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Full-text held externally
- PMID: 26267534
- UKPMCID: 26267534
- DOI: 10.1016/j.ccell.2015.07.001
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.
Bibliographic metadata
- Herrero, Ana
- Pinto, Adán
- ColĂłn-Bolea, Paula
- Casar, Berta
- Jones, Mary
- Agudo-Ibáñez, Lorena
- Vidal, Rebeca
- Tenbaum, Stephan P
- Nuciforo, Paolo
- Valdizán, Elsa M
- Horvath, Zoltan
- Orfi, Laszlo
- Pineda-Lucena, Antonio
- Bony, Emilie
- Keri, Gyorgy
- Rivas, Germán
- Pazos, Angel
- Gozalbes, Rafael
- Palmer, HĂ©ctor G
- Hurlstone, Adam
- Crespo, Piero