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.
Fuente: Cancer Cell, 2015, 28(2), 170-182
Publisher: Cell Press
Publication date: 10/08/2015
No. of pages: 13
Publication type: Article
DOI: 10.1016/j.ccell.2015.07.001.
ISSN: 1535-6108,1878-3686
Spanish project: RD/12/0036/0033 ; SAF2011-25020 ; RD12/0036/0012