Cancer-Selective Targeting of the Nf-ΚB Survival Pathway With Gadd45Β/Mkk7 Inhibitors

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Abstract

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 invitro. 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.

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Tornatore, L., Sandomenico, A., Raimondo, D., Low, C., Rocci, A., Tralau-Stewart, C., … Franzoso, G. (2014). Cancer-Selective Targeting of the Nf-ΚB Survival Pathway With Gadd45Β/Mkk7 Inhibitors. Cancer Cell, 26(4), 495–508. https://doi.org/10.1016/j.ccr.2014.07.027

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