2. Academic Validation
  3. Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes

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

  • Cancer Cell. 2015 Aug 10;28(2):170-82. doi: 10.1016/j.ccell.2015.07.001.
Ana Herrero 1,  Adán Pinto 1,  Paula Colón-Bolea 1,  Berta Casar 1,  Mary Jones 2,  Lorena Agudo-Ibáñez 1,  Rebeca Vidal 3,  Stephan P Tenbaum 4,  Paolo Nuciforo 4,  Elsa M Valdizán 3,  Zoltan Horvath 5,  Laszlo Orfi 6,  Antonio Pineda-Lucena 7,  Emilie Bony 8,  Gyorgy Keri 9,  Germán Rivas 10,  Angel Pazos 3,  Rafael Gozalbes 11,  Héctor G Palmer 4,  Adam Hurlstone 12,  Piero Crespo 13
Affiliations

Affiliations

  • 1 Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Cantabria, Santander 39011, Spain.
  • 2 Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK.
  • 3 Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Cantabria, Santander 39011, Spain; Departamento de Fisiología y Farmacología, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III Universidad de Cantabria, Santander 39011, Spain.
  • 4 Stem Cells and Cancer Laboratory, Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Barcelona 08035, Spain.
  • 5 Vichem Chemie Research Ltd., 1022 Budapest, Hungary.
  • 6 Vichem Chemie Research Ltd., 1022 Budapest, Hungary; Department of Pharmaceutical Chemistry, Semmelweis University, 1092 Budapest, Hungary.
  • 7 Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain.
  • 8 Pharmacognosy Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, 1200 Bruxelles, Belgium.
  • 9 Vichem Chemie Research Ltd., 1022 Budapest, Hungary; MTA-SE Pathobiochemistry Research Group, Department of Medical Chemistry, Semmelweis University, 1092 Budapest, Hungary.
  • 10 Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain.
  • 11 ProtoQSAR S.L., 46008 Valencia, Spain.
  • 12 Departamento de Fisiología y Farmacología, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III Universidad de Cantabria, Santander 39011, Spain.
  • 13 Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Cantabria, Santander 39011, Spain. Electronic address: crespop@unican.es.
PMID: 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.

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