Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes.
(2015) Cancer Cell — Vol. 28, n° 2, p. 170-182 (2015)
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- 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.
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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., et al. (2015). Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes. Cancer Cell, 28(2), 170-182. https://doi.org/10.1016/j.ccell.2015.07.001 (Original work published 2015)