1. Academic Validation
  2. Cancer-selective targeting of the NF-κB survival pathway with GADD45β/MKK7 inhibitors

Cancer-selective targeting of the NF-κB survival pathway with GADD45β/MKK7 inhibitors

  • Cancer Cell. 2014 Oct 13;26(4):495-508. doi: 10.1016/j.ccr.2014.07.027.
Laura Tornatore 1 Annamaria Sandomenico 2 Domenico Raimondo 3 Caroline Low 4 Alberto Rocci 5 Cathy Tralau-Stewart 4 Daria Capece 1 Daniel D'Andrea 3 Marco Bua 6 Eileen Boyle 7 Mark van Duin 8 Pietro Zoppoli 9 Albert Jaxa-Chamiec 4 Anil K Thotakura 1 Julian Dyson 10 Brian A Walker 7 Antonio Leonardi 11 Angela Chambery 12 Christoph Driessen 13 Pieter Sonneveld 8 Gareth Morgan 7 Antonio Palumbo 5 Anna Tramontano 14 Amin Rahemtulla 6 Menotti Ruvo 15 Guido Franzoso 16
Affiliations

Affiliations

  • 1 Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK.
  • 2 Institute of Biostructures and Bioimages, National Research Council and CIRPeB, 80134 Naples, Italy.
  • 3 Department of Physics, "Sapienza" University, 00185 Rome, Italy.
  • 4 Drug Discovery Centre, Imperial College London, London W6 8RP, UK.
  • 5 Division of Hematology, University of Torino, AOU San Giovanni Battista, 10126 Turin, Italy.
  • 6 Department of Medicine, Centre for Haematology, Imperial College London, London W12 0NN, UK.
  • 7 Section of Haemato-Oncology, The Institute of Cancer Research, London SM2 5NG, UK.
  • 8 Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
  • 9 Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA.
  • 10 Department of Medicine, Section of Molecular Immunology, Imperial College London, London W12 0NN, UK.
  • 11 Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II," 80131 Naples, Italy.
  • 12 Department of Environmental, Biological, and Pharmaceutical Sciences and Technologies, Second University of Naples, 81100 Caserta, Italy; IRCCS Multimedica, 20138 Milan, Italy.
  • 13 Department of Oncology/Hematology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.
  • 14 Department of Physics, "Sapienza" University, 00185 Rome, Italy; Istituto Pasteur Fondazione Cenci Bolognetti, "Sapienza" University, 00185 Rome, Italy.
  • 15 Institute of Biostructures and Bioimages, National Research Council and CIRPeB, 80134 Naples, Italy. Electronic address: menotti.ruvo@unina.it.
  • 16 Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK. Electronic address: g.franzoso@imperial.ac.uk.
Abstract

Constitutive NF-κB signaling promotes survival in multiple myeloma (MM) and other cancers; however, current NF-κB-targeting strategies lack Cancer cell specificity. Here, we identify the interaction between the NF-κB-regulated antiapoptotic factor GADD45β and the JNK kinase MKK7 as a therapeutic target in MM. Using a drug-discovery strategy, we developed DTP3, a D-tripeptide, which disrupts the GADD45β/MKK7 complex, kills MM cells effectively, and, importantly, lacks toxicity to normal cells. DTP3 has similar Anticancer potency to the clinical standard, bortezomib, but more than 100-fold higher Cancer cell specificity in vitro. Notably, DTP3 ablates myeloma xenografts in mice with no apparent side effects at the effective doses. Hence, cancer-selective targeting of the NF-κB pathway is possible and, at least for myeloma patients, promises a profound benefit.

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