Pevonedistat, a Nedd8-activating enzyme inhibitor, sensitizes neoplastic B-cells to death receptor-mediated apoptosis

Cody Paiva, J. Claire Godbersen, Taylor Rowland, Olga V. Danilova, Christopher Danes, Allison Berger, Alexey Danilov

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

While death receptor ligands (Fas and TRAIL) kill chemoresistant tumor cell lines, related therapies have limited clinical efficacy as single agents. Death receptor signaling is modulated by nuclear factor-κB (NFκB), a family of transcription factors which are constitutively active in B-cell malignancies. We and others have shown that pevonedistat, an investigational inhibitor of the NEDD8-activating enzyme, abrogates NFκB activity in B-cell neoplasia. Here we demonstrate that diffuse large B-cell lymphoma, particularly activated B-cell type, and primary chronic lymphocytic leukemia cells are re-sensitized to extrinsic apoptosis by pevonedistat. Pevonedistat enhanced caspase-8 processing following death receptor ligation, and downmodulated cFLIP, a NFκB-regulated protease-deficient caspase homolog. However, treatment with pevonedistat did not modulate death-inducing signaling complex in neoplastic B-cells, suggesting that they were sensitized to death ligands through the mitochondrial pathway. Our data provide rationale for further development of pharmacologic agents including pevonedistat in strategies which enhance death receptor signaling in lymphoid malignancies.

Original languageEnglish (US)
Pages (from-to)21128-21139
Number of pages12
JournalOncotarget
Volume8
Issue number13
DOIs
StatePublished - 2017

Fingerprint

Death Domain Receptors
Enzyme Inhibitors
B-Lymphocytes
Cell Death
Apoptosis
Death Domain Receptor Signaling Adaptor Proteins
Neoplasms
Fas Ligand Protein
Lymphoma, Large B-Cell, Diffuse
Caspase 8
B-Cell Chronic Lymphocytic Leukemia
Caspases
Tumor Cell Line
Ligation
Peptide Hydrolases
Transcription Factors
Ligands
Enzymes
Therapeutics

Keywords

  • CLL
  • Lymphoma
  • Neddylation
  • TRAIL

ASJC Scopus subject areas

  • Oncology

Cite this

Pevonedistat, a Nedd8-activating enzyme inhibitor, sensitizes neoplastic B-cells to death receptor-mediated apoptosis. / Paiva, Cody; Godbersen, J. Claire; Rowland, Taylor; Danilova, Olga V.; Danes, Christopher; Berger, Allison; Danilov, Alexey.

In: Oncotarget, Vol. 8, No. 13, 2017, p. 21128-21139.

Research output: Contribution to journalArticle

Paiva, Cody ; Godbersen, J. Claire ; Rowland, Taylor ; Danilova, Olga V. ; Danes, Christopher ; Berger, Allison ; Danilov, Alexey. / Pevonedistat, a Nedd8-activating enzyme inhibitor, sensitizes neoplastic B-cells to death receptor-mediated apoptosis. In: Oncotarget. 2017 ; Vol. 8, No. 13. pp. 21128-21139.
@article{de209fd143d84e60867c63b95bd69b30,
title = "Pevonedistat, a Nedd8-activating enzyme inhibitor, sensitizes neoplastic B-cells to death receptor-mediated apoptosis",
abstract = "While death receptor ligands (Fas and TRAIL) kill chemoresistant tumor cell lines, related therapies have limited clinical efficacy as single agents. Death receptor signaling is modulated by nuclear factor-κB (NFκB), a family of transcription factors which are constitutively active in B-cell malignancies. We and others have shown that pevonedistat, an investigational inhibitor of the NEDD8-activating enzyme, abrogates NFκB activity in B-cell neoplasia. Here we demonstrate that diffuse large B-cell lymphoma, particularly activated B-cell type, and primary chronic lymphocytic leukemia cells are re-sensitized to extrinsic apoptosis by pevonedistat. Pevonedistat enhanced caspase-8 processing following death receptor ligation, and downmodulated cFLIP, a NFκB-regulated protease-deficient caspase homolog. However, treatment with pevonedistat did not modulate death-inducing signaling complex in neoplastic B-cells, suggesting that they were sensitized to death ligands through the mitochondrial pathway. Our data provide rationale for further development of pharmacologic agents including pevonedistat in strategies which enhance death receptor signaling in lymphoid malignancies.",
keywords = "CLL, Lymphoma, Neddylation, TRAIL",
author = "Cody Paiva and Godbersen, {J. Claire} and Taylor Rowland and Danilova, {Olga V.} and Christopher Danes and Allison Berger and Alexey Danilov",
year = "2017",
doi = "10.18632/oncotarget.15050",
language = "English (US)",
volume = "8",
pages = "21128--21139",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "13",

}

TY - JOUR

T1 - Pevonedistat, a Nedd8-activating enzyme inhibitor, sensitizes neoplastic B-cells to death receptor-mediated apoptosis

AU - Paiva, Cody

AU - Godbersen, J. Claire

AU - Rowland, Taylor

AU - Danilova, Olga V.

AU - Danes, Christopher

AU - Berger, Allison

AU - Danilov, Alexey

PY - 2017

Y1 - 2017

N2 - While death receptor ligands (Fas and TRAIL) kill chemoresistant tumor cell lines, related therapies have limited clinical efficacy as single agents. Death receptor signaling is modulated by nuclear factor-κB (NFκB), a family of transcription factors which are constitutively active in B-cell malignancies. We and others have shown that pevonedistat, an investigational inhibitor of the NEDD8-activating enzyme, abrogates NFκB activity in B-cell neoplasia. Here we demonstrate that diffuse large B-cell lymphoma, particularly activated B-cell type, and primary chronic lymphocytic leukemia cells are re-sensitized to extrinsic apoptosis by pevonedistat. Pevonedistat enhanced caspase-8 processing following death receptor ligation, and downmodulated cFLIP, a NFκB-regulated protease-deficient caspase homolog. However, treatment with pevonedistat did not modulate death-inducing signaling complex in neoplastic B-cells, suggesting that they were sensitized to death ligands through the mitochondrial pathway. Our data provide rationale for further development of pharmacologic agents including pevonedistat in strategies which enhance death receptor signaling in lymphoid malignancies.

AB - While death receptor ligands (Fas and TRAIL) kill chemoresistant tumor cell lines, related therapies have limited clinical efficacy as single agents. Death receptor signaling is modulated by nuclear factor-κB (NFκB), a family of transcription factors which are constitutively active in B-cell malignancies. We and others have shown that pevonedistat, an investigational inhibitor of the NEDD8-activating enzyme, abrogates NFκB activity in B-cell neoplasia. Here we demonstrate that diffuse large B-cell lymphoma, particularly activated B-cell type, and primary chronic lymphocytic leukemia cells are re-sensitized to extrinsic apoptosis by pevonedistat. Pevonedistat enhanced caspase-8 processing following death receptor ligation, and downmodulated cFLIP, a NFκB-regulated protease-deficient caspase homolog. However, treatment with pevonedistat did not modulate death-inducing signaling complex in neoplastic B-cells, suggesting that they were sensitized to death ligands through the mitochondrial pathway. Our data provide rationale for further development of pharmacologic agents including pevonedistat in strategies which enhance death receptor signaling in lymphoid malignancies.

KW - CLL

KW - Lymphoma

KW - Neddylation

KW - TRAIL

UR - http://www.scopus.com/inward/record.url?scp=85016429902&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85016429902&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.15050

DO - 10.18632/oncotarget.15050

M3 - Article

AN - SCOPUS:85016429902

VL - 8

SP - 21128

EP - 21139

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 13

ER -