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Investigational New Drugs
Published in: Investigational New Drugs 1/2017

01-02-2017 | PRECLINICAL STUDIES

Targeting the protein ubiquitination machinery in melanoma by the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924)

Authors: Kit Man Wong, Lindsey N. Micel, Heather M. Selby, Aik Choon Tan, Todd M. Pitts, Stacey M. Bagby, Anna Spreafico, Peter J. Klauck, Stephen J. Blakemore, Peter F. Smith, Alice McDonald, Allison Berger, John J. Tentler, S. Gail Eckhardt

Published in: Investigational New Drugs | Issue 1/2017

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Abstract

Background The neddylation pathway conjugates NEDD8 to cullin-RING ligases and controls the proteasomal degradation of specific proteins involved in essential cell processes. Pevonedistat (MLN4924) is a selective small molecule targeting the NEDD8-activating enzyme (NAE) and inhibits an early step in neddylation, resulting in DNA re-replication, cell cycle arrest and death. We investigated the anti-tumor potential of pevonedistat in preclinical models of melanoma. Methods Melanoma cell lines and patient-derived tumor xenografts (PDTX) treated with pevonedistat were assessed for viability/apoptosis and tumor growth, respectively, to identify sensitive/resistant models. Gene expression microarray and gene set enrichment analyses were performed in cell lines to determine the expression profiles and pathways of sensitivity/resistance. Pharmacodynamic changes in treated-PDTX were also characterized. Results Pevonedistat effectively inhibited cell viability (IC50 < 0.3 μM) and induced apoptosis in a subset of melanoma cell lines. Sensitive and resistant cell lines exhibited distinct gene expression profiles; sensitive models were enriched for genes involved in DNA repair, replication and cell cycle regulation, while immune response and cell adhesion pathways were upregulated in resistant models. Pevonedistat also reduced tumor growth in melanoma cell line xenografts and PDTX with variable responses. An accumulation of pevonedistat-NEDD8 adduct and CDT1 was observed in sensitive tumors consistent with its mechanism of action. Conclusions This study provided preclinical evidence that NAE inhibition by pevonedistat has anti-tumor activity in melanoma and supports the clinical benefits observed in recent Phase 1 trials of this drug in melanoma patients. Further investigations are warranted to develop rational combinations and determine predictive biomarkers of pevonedistat.
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Metadata
Title
Targeting the protein ubiquitination machinery in melanoma by the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924)
Authors
Kit Man Wong
Lindsey N. Micel
Heather M. Selby
Aik Choon Tan
Todd M. Pitts
Stacey M. Bagby
Anna Spreafico
Peter J. Klauck
Stephen J. Blakemore
Peter F. Smith
Alice McDonald
Allison Berger
John J. Tentler
S. Gail Eckhardt
Publication date
01-02-2017
Publisher
Springer US
Published in
Investigational New Drugs / Issue 1/2017
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-016-0398-8

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