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

Publication

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

Journal Paper/Review - Oct 13, 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

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.