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In this study, we evaluate MLN4924 (pevonedistat); a small but potent NEDD8 pathway inhibitor. The ubiquitin protease system (UPS) is a specialized protein complex that plays an important role in the ordered degradation of apoptotic stimuli within normal and malignant cells. The NEDD8 pathway is known to be a mechanism for the downstream activation of the UPS. Therefore, we hypothesized that MLN4924 treatment would induce apoptosis in human melanoma cells. A375 and Mel39 melanoma cell lines were treated with MLN4924 alone or in combination with interferon-alfa (IFN-α) –an immune boosting agent– or vemurafenib – a novel therapeutic used to treat patients with BRAF-mutant melanoma. Treatment with MLN4924 for 72 hours induced apoptosis in both A375 and Mel39 melanoma cells with IC50s of 1200 nM and 143 nM respectively. Moreover, combination therapy of A375 cells with 104 Units/mL IFN-alfa and 1200 nM MLN4924 led to cell death levels of 78.2±3.7%, which is a significant synergistic increase compared to individual treatment by either therapeutic (p<0.005). Treatment of A375 cells with 1 μM vemurafenib had a notable effect on cell viability. However, when used in combination with MLN4924 there was an inhibitory effect on apoptosis. Results from MTS proliferation assays indicate MLN4924 does have anti-proliferation potential in melanoma cell lines, with or without the addition of IFN-alfa. A pre-treatment analysis also revealed MLN4924 led to the sensitization of A375 cells to vemurafenib treatment. Lastly, immunoblots of associate MLN4924-induced apoptosis to the cleavage of caspase-3, caspase-7, caspase-9 and PARP. These results demonstrate MLN4924 does have efficacy in treating advanced melanoma alone or in combination with IFN-alfa or vemurafenib.