title: Cancer-selective targeting of the NF-κB survival pathway with GADD45β/MKK7 inhibitors.
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.
authors.affiliation: Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Tornatore
authors.affiliation: Institute of Biostructures and Bioimages, National Research Council and CIRPeB, 80134 Naples, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Sandomenico
authors.affiliation: Department of Physics, "Sapienza" University, 00185 Rome, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Raimondo
authors.affiliation: Drug Discovery Centre, Imperial College London, London W6 8RP, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Low
authors.affiliation: Division of Hematology, University of Torino, AOU San Giovanni Battista, 10126 Turin, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Rocci
authors.affiliation: Drug Discovery Centre, Imperial College London, London W6 8RP, UK.
authors.forename: Cathy
authors.initials: C
authors.lastname: Tralau-Stewart
authors.affiliation: Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK.
authors.forename: Daria
authors.initials: D
authors.lastname: Capece
authors.affiliation: Department of Physics, "Sapienza" University, 00185 Rome, Italy.
authors.forename: Daniel
authors.initials: D
authors.lastname: D'Andrea
authors.affiliation: Department of Medicine, Centre for Haematology, Imperial College London, London W12 0NN, UK.
authors.forename: Marco
authors.initials: M
authors.lastname: Bua
authors.affiliation: Section of Haemato-Oncology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Eileen
authors.initials: E
authors.lastname: Boyle
authors.affiliation: Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: van Duin
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Pietro
authors.initials: P
authors.lastname: Zoppoli
authors.affiliation: Drug Discovery Centre, Imperial College London, London W6 8RP, UK.
authors.forename: Albert
authors.initials: A
authors.lastname: Jaxa-Chamiec
authors.affiliation: Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Thotakura
authors.affiliation: Department of Medicine, Section of Molecular Immunology, Imperial College London, London W12 0NN, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Dyson
authors.affiliation: Section of Haemato-Oncology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Walker
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II," 80131 Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Leonardi
authors.affiliation: Department of Environmental, Biological, and Pharmaceutical Sciences and Technologies, Second University of Naples, 81100 Caserta, Italy; IRCCS Multimedica, 20138 Milan, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Chambery
authors.affiliation: Department of Oncology/Hematology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Driessen
authors.affiliation: Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Sonneveld
authors.affiliation: Section of Haemato-Oncology, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Gareth
authors.initials: G
authors.lastname: Morgan
authors.affiliation: Division of Hematology, University of Torino, AOU San Giovanni Battista, 10126 Turin, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Palumbo
authors.affiliation: Department of Physics, "Sapienza" University, 00185 Rome, Italy; Istituto Pasteur Fondazione Cenci Bolognetti, "Sapienza" University, 00185 Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Tramontano
authors.affiliation: Department of Medicine, Centre for Haematology, Imperial College London, London W12 0NN, UK.
authors.forename: Amin
authors.initials: A
authors.lastname: Rahemtulla
authors.affiliation: Institute of Biostructures and Bioimages, National Research Council and CIRPeB, 80134 Naples, Italy. Electronic address: menotti.ruvo@unina.it.
authors.forename: Menotti
authors.initials: M
authors.lastname: Ruvo
authors.affiliation: Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK. Electronic address: g.franzoso@imperial.ac.uk.
authors.forename: Guido
authors.initials: G
authors.lastname: Franzoso
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D048688:MAP Kinase Kinase 7 / Q000037:antagonists & inhibitors*; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D000097642:GADD45 Proteins
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D048688:MAP Kinase Kinase 7; D016328:NF-kappa B; D009687:Nuclear Proteins; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C482569:MAP2K7 protein, human