Publikation
Cancer-Selective Targeting of the NF-κB Survival Pathway with GADD45β/MKK7 Inhibitors
Wissenschaftlicher Artikel/Review - 13.10.2014
Tornatore Laura, Dyson Julian, Walker Brian A, Leonardi Antonio, Chambery Angela, Driessen Christoph, Sonneveld Pieter, Morgan Gareth, Palumbo Antonio, Tramontano Anna, Rahemtulla Amin, Ruvo Menotti, Thotakura Anil K, Jaxa-Chamiec Albert, Sandomenico Annamaria, Raimondo Domenico, Low Caroline, Rocci Alberto, Tralau-Stewart Cathy, Capece Daria, D'Andrea Daniel, Bua Marco, Boyle Eileen, van Duin Mark, Zoppoli Pietro, Franzoso Guido
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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.