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

• Published in: Cancer cell 2014-10, Vol.26 (4), p.495-508
• Main Authors: Tornatore, Laura, 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, Jaxa-Chamiec, Albert, Thotakura, Anil K., Dyson, Julian, Walker, Brian A., Leonardi, Antonio, Chambery, Angela, Driessen, Christoph, Sonneveld, Pieter, Morgan, Gareth, Palumbo, Antonio, Tramontano, Anna, Rahemtulla, Amin, Ruvo, Menotti, Franzoso, Guido
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Biological Availability; Cell Cycle Proteins - antagonists & inhibitors; Humans; MAP Kinase Kinase 7 - antagonists & inhibitors; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; NF-kappa B - metabolism; Nuclear Proteins - antagonists & inhibitors
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2014.07.027

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. •GADD45β is a critical mediator of the NF-κB antiapoptotic function in MM•GADD45β binds to MKK7 and promotes MM cell survival by blocking MKK7/JNK signaling•GADD45β/MKK7 inhibitors display potent activity against MM, in vitro and in vivo•GADD45β/MKK7 inhibitors are far more cancer selective than IKK/NF-κB inhibitors NF-κB is implicated in MM and other malignancies, but it is challenging to block NF-κB only in diseased cells. Tornatore et al. identify an interaction between MKK7 and NF-κB-regulated GADD45β as a therapeutic target and develop a peptide that disrupts the complex and selectively kills MM cells.