MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-{kappa}B-dependent lymphoma.
MLN4924 is a potent and selective small molecule NEDD8-activating enzyme (NAE) inhibitor. In most cancer cells tested, inhibition of NAE leads to induction of DNA rereplication, resulting in DNA damage and cell death. However, in preclinical models of activated B cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), we show that MLN4924 induces an alternative mechanism of action. Treatment of ABC DLBCL cells with MLN4924 resulted in rapid accumulation of pIkappaBalpha, decrease in nuclear p65 content, reduction of nuclear factor-kappaB (NF-kappaB) transcriptional activity, and G(1) arrest, ultimately resulting in apoptosis induction, events consistent with potent NF-kappaB pathway inhibition. Treatment of germinal-center B cell-like (GCB) DLBCL cells resulted in an increase in cellular Cdt-1 and accumulation of cells in S-phase, consistent with cells undergoing DNA rereplication. In vivo administration of MLN4924 to mice bearing human xenograft tumors of ABC- and GCB-DLBCL blocked NAE pathway biomarkers and resulted in complete tumor growth inhibition. In primary human tumor models of ABC-DLBCL, MLN4924 treatment resulted in NF-kappaB pathway inhibition accompanied by tumor regressions. This work describes a novel mechanism of targeted NF-kappaB pathway modulation in DLBCL and provides strong rationale for clinical development of MLN4924 against NF-kappaB-dependent lymphomas.
Millennium Pharmaceuticals, Inc, Cambridge, MA 02139, USA.
Michael A
MA
Milhollen
Tary
T
Traore
Jennifer
J
Adams-Duffy
Michael P
MP
Thomas
Allison J
AJ
Berger
Lenny
L
Dang
Lawrence R
LR
Dick
James J
JJ
Garnsey
Erik
E
Koenig
Steven P
SP
Langston
Mark
M
Manfredi
Usha
U
Narayanan
Mark
M
Rolfe
Louis M
LM
Staudt
Teresa A
TA
Soucy
Jie
J
Yu
Julie
J
Zhang
Joseph B
JB
Bolen
Peter G
PG
Smith
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003517:Cyclopentanes / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D018858:Germinal Center / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000075687:NEDD8 Protein; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014452:Ubiquitins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D003517:Cyclopentanes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D016328:NF-kappa B; D011743:Pyrimidines; D012333:RNA, Messenger; D014452:Ubiquitins; C539933:pevonedistat