Publication

Cancer-Selective Targeting of the NF-κB Survival Pathway with GADD45β/MKK7 Inhibitors

Journal Paper/Review - Oct 13, 2014

Units
PubMed
Doi

Citation
Tornatore L, Dyson J, Walker B, Leonardi A, Chambery A, Driessen C, Sonneveld P, Morgan G, Palumbo A, Tramontano A, Rahemtulla A, Ruvo M, Thotakura A, Jaxa-Chamiec A, Sandomenico A, Raimondo D, Low C, Rocci A, Tralau-Stewart C, Capece D, D'Andrea D, Bua M, Boyle E, van Duin M, Zoppoli P, Franzoso G. Cancer-Selective Targeting of the NF-κB Survival Pathway with GADD45β/MKK7 Inhibitors. Cancer Cell 2014; 26:495-508.
Type
Journal Paper/Review (English)
Journal
Cancer Cell 2014; 26
Publication Date
Oct 13, 2014
Issn Electronic
1878-3686
Pages
495-508
Brief description/objective

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.