title: Targeting the protein ubiquitination machinery in melanoma by the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924).
abstract: Background The neddylation pathway conjugates NEDD8 to cullin-RING ligases and controls the proteasomal degradation of specific proteins involved in essential cell processes. Pevonedistat (MLN4924) is a selective small molecule targeting the NEDD8-activating enzyme (NAE) and inhibits an early step in neddylation, resulting in DNA re-replication, cell cycle arrest and death. We investigated the anti-tumor potential of pevonedistat in preclinical models of melanoma. Methods Melanoma cell lines and patient-derived tumor xenografts (PDTX) treated with pevonedistat were assessed for viability/apoptosis and tumor growth, respectively, to identify sensitive/resistant models. Gene expression microarray and gene set enrichment analyses were performed in cell lines to determine the expression profiles and pathways of sensitivity/resistance. Pharmacodynamic changes in treated-PDTX were also characterized. Results Pevonedistat effectively inhibited cell viability (IC50< 0.3 μM) and induced apoptosis in a subset of melanoma cell lines. Sensitive and resistant cell lines exhibited distinct gene expression profiles; sensitive models were enriched for genes involved in DNA repair, replication and cell cycle regulation, while immune response and cell adhesion pathways were upregulated in resistant models. Pevonedistat also reduced tumor growth in melanoma cell line xenografts and PDTX with variable responses. An accumulation of pevonedistat-NEDD8 adduct and CDT1 was observed in sensitive tumors consistent with its mechanism of action. Conclusions This study provided preclinical evidence that NAE inhibition by pevonedistat has anti-tumor activity in melanoma and supports the clinical benefits observed in recent Phase 1 trials of this drug in melanoma patients. Further investigations are warranted to develop rational combinations and determine predictive biomarkers of pevonedistat.
authors: Division of Medical Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, WA.
authors: Kit Man
authors: KM
authors: Wong
authors: Developmental Therapeutics Program, Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO.
authors: Lindsey N
authors: LN
authors: Micel
authors: Developmental Therapeutics Program, Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO.
authors: Heather M
authors: HM
authors: Selby
authors: Developmental Therapeutics Program, Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO.|University of Colorado Cancer Center, Aurora, CO.
authors: Aik Choon
authors: AC
authors: Tan
authors: Developmental Therapeutics Program, Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO.|University of Colorado Cancer Center, Aurora, CO.
authors: Todd M
authors: TM
authors: Pitts
authors: Developmental Therapeutics Program, Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO.
authors: Stacey M
authors: SM
authors: Bagby
authors: Department of Medical Oncology, Princess Margaret Cancer Center, Toronto, ON.
authors: Anna
authors: A
authors: Spreafico
authors: Developmental Therapeutics Program, Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO.
authors: Peter J
authors: PJ
authors: Klauck
authors: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA.
authors: Stephen J
authors: SJ
authors: Blakemore
authors: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA.
authors: Peter F
authors: PF
authors: Smith
authors: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA.
authors: Alice
authors: A
authors: McDonald
authors: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA.
authors: Allison
authors: A
authors: Berger
authors: Developmental Therapeutics Program, Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO.|University of Colorado Cancer Center, Aurora, CO.
authors: John J
authors: JJ
authors: Tentler
authors: Developmental Therapeutics Program, Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO.|University of Colorado Cancer Center, Aurora, CO.
authors: S Gail
authors: SG
authors: Eckhardt
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003517:Cyclopentanes / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D003517:Cyclopentanes; D011743:Pyrimidines; D044764:Ubiquitin-Activating Enzymes; C491802:NAE protein, human; C539933:pevonedistat
keywords: MLN4924; Melanoma; Neddylation; Pevonedistat; Protein degradation