Cancer-selective targeting of the NF-κB survival pathway with GADD45β/MKK7 inhibitors.
Bottom Line: 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.Hence, cancer-selective targeting of the NF-κB pathway is possible and, at least for myeloma patients, promises a profound benefit.
Affiliation: Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK.Show MeSH
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Mentions: Importantly, DTP3 retained potent anticancer activity in an orthotopic xenograft model of MM, which more faithfully recapitulates the human disease. All the control mice developed severe limb paralysis and died within 32 days of treatment start, resulting in a median OS of 26 days (Figure 7F). Strikingly, DTP3 administration over a period of 8 weeks, at a dose of 29 mg/kg/day, extended the median OS of the mice past the experimental end point on day 161, without producing any apparent side effect, thus demonstrating the potent therapeutic efficacy of DTP3 against MM, in vivo, and the excellent tolerability of this agent at doses that achieve full therapeutic efficacy. Collectively, together with the data in primary MM cells (Figures 6A–6D; Figures S6A and S6B), these results underscore the potency, safety, and cancer cell specificity of the pharmacological approach targeting the GADD45β/MKK7 complex in MM and identify DTP3 as a therapeutic selectively inhibiting the NF-κB survival pathway in cancer (Figure 8).
Affiliation: Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK.