title: Pevonedistat, a NEDD8-activating enzyme inhibitor, is active in mantle cell lymphoma and enhances rituximab activity in vivo.
abstract: Mantle cell lymphoma (MCL) is characterized by an aggressive clinical course and inevitable development of refractory disease, stressing the need to develop alternative therapeutic strategies. To this end, we evaluated pevonedistat (MLN4924), a novel potent and selective NEDD8-activating enzyme inhibitor in a panel of MCL cell lines, primary MCL tumor cells, and 2 distinct murine models of human MCL. Pevonedistat exposure resulted in a dose-, time-, and caspase-dependent cell death in the majority of the MCL cell lines and primary tumor cells tested. Of interest, in the MCL cell lines with lower half-maximal inhibitory concentration (0.1-0.5 μM), pevonedistat induced G1-phase cell cycle arrest, downregulation of Bcl-xL levels, decreased nuclear factor (NF)-κB activity, and apoptosis. In addition, pevonedistat exhibited additive/synergistic effects when combined with cytarabine, bendamustine, or rituximab. In vivo, as a single agent, pevonedistat prolonged the survival of 2 MCL-bearing mouse models when compared with controls. Pevonedistat in combination with rituximab led to improved survival compared with rituximab or pevonedistat monotherapy. Our data suggest that pevonedistat has significant activity in MCL preclinical models, possibly related to effects on NF-κB activity, Bcl-xL downregulation, and G1 cell cycle arrest. Our findings support further investigation of pevonedistat with or without rituximab in the treatment of MCL.
authors.affiliation: Department of Pediatrics, Departments of Medicine and Immunology.
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Czuczman
authors.affiliation: Department of Pediatrics, Departments of Medicine and Immunology.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Barth
authors.affiliation: Departments of Medicine and Immunology.
authors.forename: Juan
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Pathology, and.
authors.forename: Vishala
authors.initials: V
authors.lastname: Neppalli
authors.affiliation: Departments of Medicine and Immunology.
authors.forename: Cory
authors.initials: C
authors.lastname: Mavis
authors.affiliation: Department of Pediatrics, Departments of Medicine and Immunology.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Frys
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY;
authors.forename: Qiang
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY;
authors.forename: Song
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, University of Buffalo, Buffalo, NY; and Clinical Department of Hematology, Institute of Pathophysiology, Charles University in Prague, Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Klener
authors.affiliation: Department of Pediatrics, University of Buffalo, Buffalo, NY; and Clinical Department of Hematology, Institute of Pathophysiology, Charles University in Prague, Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Vockova
authors.affiliation: Departments of Medicine and Immunology.
authors.forename: Myron S
authors.initials: MS
authors.lastname: Czuczman
authors.affiliation: Departments of Medicine and Immunology.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Hernandez-Ilizaliturri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D003517:Cyclopentanes / Q000494:pharmacology / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016513:Mice, SCID; D000075687:NEDD8 Protein; D016328:NF-kappa B / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D000069283:Rituximab / Q000494:pharmacology / Q000627:therapeutic use*; D054852:Small Molecule Libraries / Q000494:pharmacology / Q000627:therapeutic use; D014452:Ubiquitins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D054852:Small Molecule Libraries; D014452:Ubiquitins; D000069283:Rituximab; D020169:Caspases; C539933:pevonedistat