Targeting GADD45β/MKK7 Downstream of NFκB Induces Cancer-Specific Apoptosis

Many cancers, including multiple myeloma, exhibit aberrant activation of NFκB signaling, which promotes cancer-cell survival via the upregulation of antiapoptotic genes and renders cells sensitive to NFκB inhibition. However, to date, no NFκB-targeted therapies have been clinically approved due to toxicities associated with global NFκB inhibition, underscoring the need to develop strategies to selectively inhibit cancer-specific NFκB signaling. Tornatore and colleagues found that expression of the NFκB target gene growth arrest and DNA-damage–inducible β (GADD45B), which encodes an inhibitor of the JNK kinase MKK7 (also known as MAP2K7), was elevated in plasma cells from patients with multiple myeloma and was correlated with decreased survival. GADD45β was essential for NFκB-mediated survival of multiple myeloma cells through inhibition of MKK7–JNK-driven apoptosis, suggesting GADD45β as a potential therapeutic target. A peptide library screen identified two acetylated L-tetrapeptides that disrupted the GADD45β/MKK7 complex in vitro. Synthesis of the corresponding D-tetrapeptides and subsequent chemical optimization yielded DTP3, a highly stable D-tripeptide with improved bioavailability that interacted specifically with MKK7 to activate JNK signaling and induce cancer-cell–specific apoptosis in a dose-dependent manner. DTP3 also displayed potent and selective activity in various cancer cell lines with high GADD45B expression. Importantly, DTP3 was cytotoxic to primary myeloma cells from patients at low concentrations and without toxicity to normal cells, resulting in a greater therapeutic index compared with bortezomib, the current standard treatment for multiple myeloma. In addition, DTP3 synergized with bortezomib and was effective in multiple myeloma cells that were resistant to conventional treatments. Furthermore, DTP3 was well tolerated, induced tumor shrinkage, and extended survival in mouse models of multiple myeloma. These data identify the GADD45β/MKK7 complex as a critical mediator of NFκB-induced survival and demonstrate a therapeutic strategy to selectively inhibit NFκB signaling in cancer cells using DTP3.

Tornatore L, Sandomenico A, Raimondo D, Low C, Rocci A, Tralau-Stewart C, et al. Cancer-selective targeting of the NFκB survival pathway with GADD45β/MKK7 inhibitors. Cancer Cell 2014;26:495–508.

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