Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes

Ana Herrero, Adán Pinto, Paula Colón-Bolea, Berta Casar, Mary Jones, Lorena Agudo-Ibáñez, Rebeca Vidal, Stephan P. Tenbaum, Paolo Nuciforo, Elsa M. Valdizán, Zoltan Horvath, L. Őrfi, Antonio Pineda-Lucena, Emilie Bony, G. Kéri, Germán Rivas, Angel Pazos, Rafael Gozalbes, Héctor G. Palmer, Adam HurlstonePiero Crespo

Research output: Contribution to journalArticle

55 Citations (Scopus)

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. Herrero et al. identify a small molecule inhibitor of ERK dimerization that impedes the growth of tumor cells dependent on a hyperactivated RAS-ERK pathway. Importantly, the antitumor effect of this compound in cells is not affected by the reported resistance mechanisms for the current BRAF and MEK inhibitors.

Original languageEnglish
Pages (from-to)170-182
Number of pages13
JournalCancer Cell
Volume28
Issue number2
DOIs
Publication statusPublished - Aug 10 2015

Fingerprint

MAP Kinase Signaling System
Dimerization
Oncogenes
Carcinogenesis
Antineoplastic Agents
Neoplasms
Mitogen-Activated Protein Kinase Kinases
Protein Transport
Phosphorylation
Growth
Proteins
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Herrero, A., Pinto, A., Colón-Bolea, P., Casar, B., Jones, M., Agudo-Ibáñez, L., ... Crespo, P. (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

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; Őrfi, L.; Pineda-Lucena, Antonio; Bony, Emilie; Kéri, G.; Rivas, Germán; Pazos, Angel; Gozalbes, Rafael; Palmer, Héctor G.; Hurlstone, Adam; Crespo, Piero.

In: Cancer Cell, Vol. 28, No. 2, 10.08.2015, p. 170-182.

Research output: Contribution to journalArticle

Herrero, A, Pinto, A, Colón-Bolea, P, Casar, B, Jones, M, Agudo-Ibáñez, L, Vidal, R, Tenbaum, SP, Nuciforo, P, Valdizán, EM, Horvath, Z, Őrfi, L, Pineda-Lucena, A, Bony, E, Kéri, G, Rivas, G, Pazos, A, Gozalbes, R, Palmer, HG, Hurlstone, A & Crespo, P 2015, 'Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes', Cancer Cell, vol. 28, no. 2, pp. 170-182. https://doi.org/10.1016/j.ccell.2015.07.001
Herrero A, Pinto A, Colón-Bolea P, Casar B, Jones M, Agudo-Ibáñez L et al. Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes. Cancer Cell. 2015 Aug 10;28(2):170-182. https://doi.org/10.1016/j.ccell.2015.07.001
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 ; Őrfi, L. ; Pineda-Lucena, Antonio ; Bony, Emilie ; Kéri, G. ; Rivas, Germán ; Pazos, Angel ; Gozalbes, Rafael ; Palmer, Héctor G. ; Hurlstone, Adam ; Crespo, Piero. / Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes. In: Cancer Cell. 2015 ; Vol. 28, No. 2. pp. 170-182.
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