Inhibition of NEDD8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia

Author:

Swords Ronan T.1,Kelly Kevin R.1,Smith Peter G.2,Garnsey James J.2,Mahalingam Devalingam1,Medina Ernest1,Oberheu Kelli1,Padmanabhan Swaminathan1,O'Dwyer Michael3,Nawrocki Steffan T.1,Giles Francis J.1,Carew Jennifer S.1

Affiliation:

1. Institute for Drug Development, Cancer Therapy and Research Center at the University of Texas Health Science Center at San Antonio;

2. Millennium Pharmaceuticals, Cambridge, MA; and

3. University College Hospital, Galway, Ireland

Abstract

Abstract 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-κB 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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