Cancer-Selective Targeting of the NF-kappa B Survival Pathway with GADD45 beta/MKK7 Inhibitors

L Tornatore, A Sandomenico, D Raimondo, C Low, A Rocci, C Tralau-Stewart, D Capece, D D'Andrea, M Bua, E Boyle, Mark van Duin, P Zoppoli, A Jaxa-Chamiec, AK Thotakura, J Dyson, BA Walker, A Leonardi, A Chambery, Caroline Driessen, Pieter SonneveldG Morgan, A Palumbo, A Tramontano, A Rahemtulla, M Ruvo, G Franzoso

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Abstract

Constitutive NF-B-K signaling promotes survival in multiple myeloma (MM) and other cancers; however, current NF-B-K-targeting strategies lack cancer cell specificity. Here, we identify the interaction between the NF-B-K-regulated antiapoptotic factor GADD45 beta 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 GADD45 beta/ 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 rnyeloma xenografts in mice with no apparent side effects at the effective doses. Hence, cancer-selective targeting of the NF-KB pathway is possible and, at least for myeloma patients, promises a profound benefit.
Original languageUndefined/Unknown
Pages (from-to)495-508
Number of pages14
JournalCancer Cell
Volume26
Issue number4
DOIs
Publication statusPublished - 2014

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