Cancer-selective targeting of the NF-κB survival pathway with GADD45β/MKK7 inhibitors PMID: 25314077

ADC Targets in Oncology

2026-04-10

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

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: [email protected].
16. Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK. Electronic address: [email protected].

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.