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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1-15
Number of pages15
JournalInvestigational New Drugs
DOIs
Publication statusAccepted/In press - 2016 Oct 25
Externally publishedYes

Fingerprint

Ubiquitination
Enzyme Inhibitors
Protein Transport
Melanoma
Heterografts
Neoplasms
Cell Line
DNA Replication
Cullin Proteins
Apoptosis
((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo(2,3-d)pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulphamate
Enzymes
Ligases
Growth
Cell Cycle Checkpoints
Transcriptome
Cell Adhesion
DNA Repair
Proteolysis
Genes

Keywords

  • Melanoma
  • MLN4924
  • Neddylation
  • Pevonedistat
  • Protein degradation

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Wong, K. M., Micel, L. N., Selby, H. M., Tan, A-C., Pitts, T. M., Bagby, S. M., ... Eckhardt, S. G. (Accepted/In press). Targeting the protein ubiquitination machinery in melanoma by the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924). Investigational New Drugs, 1-15. https://doi.org/10.1007/s10637-016-0398-8

Targeting the protein ubiquitination machinery in melanoma by the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924). / Wong, Kit Man; Micel, Lindsey N.; Selby, Heather M.; Tan, Aik-Choon; Pitts, Todd M.; Bagby, Stacey M.; Spreafico, Anna; Klauck, Peter J.; Blakemore, Stephen J.; Smith, Peter F.; McDonald, Alice; Berger, Allison; Tentler, John J.; Eckhardt, S. Gail.

In: Investigational New Drugs, 25.10.2016, p. 1-15.

Research output: Contribution to journalArticle

Wong, KM, Micel, LN, Selby, HM, Tan, A-C, Pitts, TM, Bagby, SM, Spreafico, A, Klauck, PJ, Blakemore, SJ, Smith, PF, McDonald, A, Berger, A, Tentler, JJ & Eckhardt, SG 2016, 'Targeting the protein ubiquitination machinery in melanoma by the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924)', Investigational New Drugs, pp. 1-15. https://doi.org/10.1007/s10637-016-0398-8
Wong, Kit Man ; Micel, Lindsey N. ; Selby, Heather M. ; Tan, Aik-Choon ; Pitts, Todd M. ; Bagby, Stacey M. ; Spreafico, Anna ; Klauck, Peter J. ; Blakemore, Stephen J. ; Smith, Peter F. ; McDonald, Alice ; Berger, Allison ; Tentler, John J. ; Eckhardt, S. Gail. / Targeting the protein ubiquitination machinery in melanoma by the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924). In: Investigational New Drugs. 2016 ; pp. 1-15.
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T1 - Targeting the protein ubiquitination machinery in melanoma by the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924)

AU - Wong, Kit Man

AU - Micel, Lindsey N.

AU - Selby, Heather M.

AU - Tan, Aik-Choon

AU - Pitts, Todd M.

AU - Bagby, Stacey M.

AU - Spreafico, Anna

AU - Klauck, Peter J.

AU - Blakemore, Stephen J.

AU - Smith, Peter F.

AU - McDonald, Alice

AU - Berger, Allison

AU - Tentler, John J.

AU - Eckhardt, S. Gail

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N2 - 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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KW - Protein degradation

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