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

Abstract

SummaryConstitutive 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 Loss Ablates Innate Immunosuppression in Cancer

“…Using three distinct models of solid cancers that are largely refractory to immunotherapies, including hepatocellular carcinoma (HCC) and ovarian adenocarcinoma, we showed that Gadd45b deletion in myeloid cells restores proinflammatory TAM activation and intratumoural CD8 + T-lymphocyte infiltration, resulting in diminished tumour growth. Since we previously showed that GADD45β additionally mediates the NF-κB antiapoptotic activity in cancer cells (24), our current findings identify GADD45β as a pivotal downstream hub integrating the NF-κB oncogenic functions linking cancer and inflammation. Our finding that elevated GADD45B expression correlates with poor clinical outcomes across most human cancers consolidates the general clinical significance of the GADD45β-mediated oncogenic mechanism in malignant disease.…”

“…We recently identified the product of the NF-κB-regulated gene, GADD45B , as an essential survival factor and novel therapeutic target in multiple myeloma (24). We therefore investigated whether GADD45B was involved in any types of malignancy beyond multiple myeloma.…”

“…Once tumours became palpable, tumour growth was monitored every other day using a vernier caliper. Tumour volumes were calculated using the formula: volume = AxB 2 /2 (where A is the larger diameter, and B is the smaller diameter of the tumour) (24). 19 days after tumour cell injection, mice were sacrificed, and tumours were removed and embedded in Tissue-Tek OCT compound (Sakura Finetek) for frozen block preparation.…”

Proteasome inhibitor-adapted myeloma cells are largely independent from proteasome activity and show complex proteomic changes, in particular in redox and energy metabolism

“…Proteasome inhibitor-resistant cell lines generated in vitro by continuous exposure to proteasome-inhibiting drugs serve as models to understand and potentially overcome proteasome inhibitor resistance. 14, 15, 16 Mutations in PSMB5 (encoding for β5c) were predicted to lead to impaired inhibitor binding owing to changes in the β5c active site or the inhibitor-binding pocket. 14, 17, 18 However, the functional relevance of such mutations on the active site binding of bortezomib or carfilzomib in MM cells has not been demonstrated, and extensive analysis in MM cells derived from patients resistant to proteasome inhibitor therapy failed to identify such PSMB5 mutations.…”

Potential Therapeutic Effects of Natural Extracts in Multiple Myeloma

“…The best documented function of NF-κB in cancer is to induce genes that block apoptosis and, despite its ubiquitous nature, NF-κB signaling elicits highly tissue-and context-specific transcriptional programs [66] . When compared to chemosensitive MM cell lines chemoresistant MM cells express higher levels of NF-κB, suggesting a link between NF-κB and development of chemoresistance [67] .…”