Investigational New Drugs

, Volume 35, Issue 1, pp 11–25

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

  • 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
PRECLINICAL STUDIES

DOI: 10.1007/s10637-016-0398-8

Cite this article as:
Wong, K.M., Micel, L.N., Selby, H.M. et al. Invest New Drugs (2017) 35: 11. doi:10.1007/s10637-016-0398-8

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.

Keywords

Neddylation Pevonedistat MLN4924 Protein degradation Melanoma 

Supplementary material

10637_2016_398_MOESM1_ESM.docx (3.9 mb)
ESM 1(DOCX 4003 kb)

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Kit Man Wong
    • 1
  • Lindsey N. Micel
    • 2
  • Heather M. Selby
    • 2
  • Aik Choon Tan
    • 2
    • 3
  • Todd M. Pitts
    • 2
    • 3
  • Stacey M. Bagby
    • 2
  • Anna Spreafico
    • 4
  • Peter J. Klauck
    • 2
  • Stephen J. Blakemore
    • 5
  • Peter F. Smith
    • 5
  • Alice McDonald
    • 5
  • Allison Berger
    • 5
  • John J. Tentler
    • 2
    • 3
  • S. Gail Eckhardt
    • 2
    • 3
  1. 1.Division of Medical Oncology, Department of MedicineUniversity of Washington School of MedicineSeattleUSA
  2. 2.Developmental Therapeutics Program, Division of Medical Oncology, Department of MedicineUniversity of Colorado Anschutz Medical CampusAuroraUSA
  3. 3.University of Colorado Cancer CenterAuroraUSA
  4. 4.Department of Medical Oncology, Princess Margaret Cancer CenterTorontoCanada
  5. 5.Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company LtdCambridgeUSA

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