title: Molecular and cellular effects of NEDD8-activating enzyme inhibition in myeloma.
abstract: The NEDD8-activating enzyme is upstream of the 20S proteasome in the ubiquitin/proteasome pathway and catalyzes the first step in the neddylation pathway. NEDD8 modification of cullins is required for ubiquitination of cullin-ring ligases that regulate degradation of a distinct subset of proteins. The more targeted impact of NEDD8-activating enzyme on protein degradation prompted us to study MLN4924, an investigational NEDD8-activating enzyme inhibitor, in preclinical multiple myeloma models. In vitro treatment with MLN4924 led to dose-dependent decrease of viability (EC(50) = 25-150 nmol/L) in a panel of human multiple myeloma cell lines. MLN4924 was similarly active against a bortezomib-resistant ANBL-6 subline and its bortezomib-sensitive parental cells. MLN4924 had submicromolar activity (EC(50) values <500 nmol/L) against primary CD138(+) multiple myeloma patient cells and exhibited at least additive effect when combined with dexamethasone, doxorubicin, and bortezomib against MM.1S cells. The bortezomib-induced compensatory upregulation of transcripts for ubiquitin/proteasome was not observed with MLN4924 treatment, suggesting distinct functional roles of NEDD8-activating enzyme versus 20S proteasome. MLN4924 was well tolerated at doses up to 60 mg/kg 2× daily and significantly reduced tumor burden in both a subcutaneous and an orthotopic mouse model of multiple myeloma. These studies provide the framework for the clinical investigation of MLN4924 in multiple myeloma.
authors.affiliation: Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: McMillin
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Jacobs
authors.forename: Jake E
authors.initials: JE
authors.lastname: Delmore
authors.forename: Leutz
authors.initials: L
authors.lastname: Buon
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Hunter
authors.forename: Val
authors.initials: V
authors.lastname: Monrose
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.forename: Peter G
authors.initials: PG
authors.lastname: Smith
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Steven P
authors.initials: SP
authors.lastname: Treon
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D000075687:NEDD8 Protein; D011719:Pyrazines / Q000494:pharmacology; D016896:Treatment Outcome; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054875:Ubiquitination; D014452:Ubiquitins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D001897:Boronic Acids; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011719:Pyrazines; D014452:Ubiquitins; D000069286:Bortezomib; D044764:Ubiquitin-Activating Enzymes