Inhibition of NEDD8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia.
NEDD8 activating enzyme (NAE) has been identified as an essential regulator of the NEDD8 conjugation pathway, which controls the degradation of many proteins with important roles in cell-cycle progression, DNA damage, and stress responses. Here we report that MLN4924, a novel inhibitor of NAE, has potent activity in acute myeloid leukemia (AML) models. MLN4924 induced cell death in AML cell lines and primary patient specimens independent of Fms-like tyrosine kinase 3 expression and stromal-mediated survival signaling and led to the stabilization of key NAE targets, inhibition of nuclear factor-kappaB activity, DNA damage, and reactive oxygen species generation. Disruption of cellular redox status was shown to be a key event in MLN4924-induced apoptosis. Administration of MLN4924 to mice bearing AML xenografts led to stable disease regression and inhibition of NEDDylated cullins. Our findings indicate that MLN4924 is a highly promising novel agent that has advanced into clinical trials for the treatment of AML.
Swords
Ronan T
RT
Institute for Drug Development, Cancer Therapy and Research Center at the University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
Kelly
Kevin R
KR
Smith
Peter G
PG
Garnsey
James J
JJ
Mahalingam
Devalingam
D
Medina
Ernest
E
Oberheu
Kelli
K
Padmanabhan
Swaminathan
S
O'Dwyer
Michael
M
Nawrocki
Steffan T
ST
Giles
Francis J
FJ
Carew
Jennifer S
JS
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D044842:Cullin Proteins; D003517:Cyclopentanes / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051379:Mice; D000075687:NEDD8 Protein; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014452:Ubiquitins / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism
D044842:Cullin Proteins; D003517:Cyclopentanes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014452:Ubiquitins; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D046988:Proteasome Endopeptidase Complex; C539933:pevonedistat