The NAE inhibitor pevonedistat (MLN4924) synergizes with TNF-α to activate apoptosis

Abstract

Predicting and understanding the mechanism of drug-induced toxicity is one of the primary goals of drug development. It has been hypothesized that inflammation may have a synergistic role in this process. Cell-based models provide an easily manipulated system to investigate this type of drug toxicity. Several groups have attempted to reproduce in vivo toxicity with combination treatment of pharmacological agents and inflammatory cytokines. Through this approach, synergistic cytotoxicity between the investigational agent pevonedistat (MLN4924) and TNF-α was identified. Pevonedistat is an inhibitor of the NEDD8-activating enzyme (NAE). Inhibition of NAE prevents activation of cullin-RING ligases, which are critical for proteasome-mediated protein degradation. TNF-α is a cytokine that is involved in inflammatory responses and cell death, among other biological functions. Treatment of cultured cells with the combination of pevonedistat and TNF-α, but not as single agents, resulted in rapid cell death. This cell death was determined to be mediated by caspase-8. Interestingly, the combination treatment of pevonedistat and TNF-α also caused an accumulation of the p10 protease subunit of caspase-8 that was not observed with cytotoxic doses of TNF-α. Under conditions where apoptosis was blocked, the mechanism of death switched to necroptosis. Trimerized MLKL was verified as a biomarker of necroptotic cell death. The synergistic toxicity of pevonedistat and elevated TNF-α was also demonstrated by in vivo rat studies. Only the combination treatment resulted in elevated serum markers of liver damage and single-cell hepatocyte necrosis. Taken together, the results of this work have characterized a novel synergistic toxicity driven by pevonedistat and TNF-α.

The NEDD8-activating enzyme inhibitor MLN4924 sensitizes a TNFR1+ subgroup of multiple myeloma cells for TNF-induced cell death

“…MLN4924 therefore acts as an inhibitor of TNF-induced NFκB activation downstream of the activation of the IKK complex. In accordance with the fact that TNFR1-induced NFκB signaling contributes to cell death resistance against TNF, we and others reported that MLN4924 can sensitize cells for the cytotoxic activities of TNF 19,20 . MLN4924 is currently under consideration in a variety of clinical trials including phase 1 studies with patients suffering on acute myeloid leukemia, myelodysplastic syndromes, metastatic melanoma, relapsed/refractory MM or lymphoma and solid cancer 37–42 .…”

“…At the molecular level, the anti-tumoral effects of MLN4924 have been traced back to the inhibition of the proteasomal degradation of various negative regulators of the DNA damage response, the cell cycle and senescence 17 . Recently, it was proved by us and others that MLN4924 enhances TNF-induced cell death 19,20 . As far as proteasome targeting drugs are successfully used to treat MM, an alternative strategy to target the ubiquitin-proteasome pathway in MM might lay in the inhibition of NAE by MLN4924.…”

Expanded safety analysis of pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukemia and myelodysplastic syndromes

“…It is interesting to speculate that transient leakage of transaminases from edematous hepatocytes in treated patients may have accounted for some of the laboratory toxicities observed in this study. A more compelling perspective on pevonedistat-induced liver toxicity was presented by Wolenski et al , 12 who demonstrated that treatment with pevonedistat lowered the activation threshold for tumor necrosis factor (TNF)-mediated cell death, by conferring cellular sensitivity to low concentrations of TNF-α. Patients with higher circulating levels of TNF-α (typically the case during sepsis) treated with pevonedistat in our study may have been more prone to the tissue-damaging effects of this cytokine.…”

Phase I study assessing the mass balance, pharmacokinetics, and excretion of [14C]-pevonedistat, a NEDD8-activating enzyme inhibitor in patients with advanced solid tumors

“…Pevonedistat (TAK-924/MLN4924) is an investigational small-molecule inhibitor of the neural precursor cellexpressed, developmentally down-regulated 8 (NEDD8)-activating enzyme (NAE) [1,2]. NAE conjugates NEDD8 t o c u l l i n -R I N G l i g a s e s ( C R L s ) , w h i c h c o n t r o l ubiquitination and proteasomal degradation of substrates involved in cell cycle progression (p21, p27, and cyclin D/E), DNA replication (CDT1), oxidative response (NFR2), and response to hypoxia (HIF1a) [3,4].…”

“…Accumulating evidence also suggests that neddylation has a pivotal role in regulating immune cell function and tumor angiogenesis in the tumor microenvironment [7]. Moreover, pevonedistat also blocks prosurvival signaling by NF-κB [1,8]. Dysfunction of the NEDD8 cascade is linked to the pathogenesis of several diseases, including cancer, making it a compelling target for drug development [7,9].…”