Deneddylation of ribosomal proteins promotes synergy between MLN4924 and chemotherapy to elicit complete therapeutic responses.

Topotecan Tumor Suppressor Protein p53 bcl-2-Associated X Protein Cell Line, Tumor Cyclopentanes / pharmacology Ribosomal Proteins Apoptosis NEDD8 Protein
CP: Cancer MYCN RPL11 melphalan multiple myeloma nucleoli p53 pevonedistat retinoblastoma synergy topotecan

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
29 08 2023
Historique:
received: 14 11 2022
revised: 29 05 2023
accepted: 18 07 2023
medline: 4 9 2023
pubmed: 8 8 2023
entrez: 8 8 2023
Statut: ppublish

Résumé

The neddylation inhibitor MLN4924/Pevonedistat is in clinical trials for multiple cancers. Efficacy is generally attributed to cullin RING ligase (CRL) inhibition, but the contribution of non-CRL targets is unknown. Here, CRISPR screens map MLN4924-monotherapy sensitivity in retinoblastoma to a classic DNA damage-induced p53/E2F3/BAX-dependent death effector network, which synergizes with Nutlin3a or Navitoclax. In monotherapy-resistant cells, MLN4924 plus standard-of-care topotecan overcomes resistance, but reduces DNA damage, instead harnessing ribosomal protein nucleolar-expulsion to engage an RPL11/p21/MYCN/E2F3/p53/BAX synergy network that exhibits extensive cross-regulation. Strikingly, unneddylatable RPL11 substitutes for MLN4924 to perturb nucleolar function and enhance topotecan efficacy. Orthotopic tumors exhibit complete responses while preserving visual function. Moreover, MLN4924 plus melphalan deploy this DNA damage-independent strategy to synergistically kill multiple myeloma cells. Thus, MLN4924 synergizes with standard-of-care drugs to unlock a nucleolar death effector network across cancer types implying broad therapeutic relevance.

Identifiants

DOI: 10.1016/j.celrep.2023.112925 PMID: 37552601
pubmed: 37552601
pii: S2211-1247(23)00936-1
doi: 10.1016/j.celrep.2023.112925
pii:
doi:

Substances chimiques

pevonedistat S3AZD8D215
Topotecan 7M7YKX2N15
Tumor Suppressor Protein p53 0
bcl-2-Associated X Protein 0
Cyclopentanes 0
Ribosomal Proteins 0
NEDD8 Protein 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

112925

Subventions

Organisme : CIHR
ID : 173474
Pays : Canada

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

Auteurs

Arthur Aubry (A)

Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada; Department of Lab Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Centre Hospitalo-universitaire (CHU) de Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole (IUCT-O), Université de Toulouse, UPS, Unité de Génomique du Myélome, Toulouse, France.

Joel D Pearson (JD)

Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada.

Jason Charish (J)

Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON, Canada; Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, ON, Canada.

Tao Yu (T)

Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada.

Jeremy M Sivak (JM)

Department of Lab Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON, Canada; Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, ON, Canada.

Dimitris P Xirodimas (DP)

CRBM, University Montpellier, CNRS, Montpellier, France.

Hervé Avet-Loiseau (H)

Centre Hospitalo-universitaire (CHU) de Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole (IUCT-O), Université de Toulouse, UPS, Unité de Génomique du Myélome, Toulouse, France; Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM, Toulouse, France.

Jill Corre (J)

Centre Hospitalo-universitaire (CHU) de Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole (IUCT-O), Université de Toulouse, UPS, Unité de Génomique du Myélome, Toulouse, France; Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM, Toulouse, France.

Philippe P Monnier (PP)

Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON, Canada; Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, ON, Canada.

Rod Bremner (R)

Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada; Department of Lab Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON, Canada. Electronic address: bremner@lunenfeld.ca.

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Classifications MeSH

questionsmedicales.fr › Composés hétérocycliques › Alcaloïdes › Camptothécine › Topotécane › Deneddylation of ribosomal proteins promotes...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Phosphoprotéines › Protéine p53 suppresseur de tumeur › Deneddylation of ribosomal proteins promotes...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines régulatrices de l'apoptose › Protéine Bax › Deneddylation of ribosomal proteins promotes...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Deneddylation of ribosomal proteins promotes...
questionsmedicales.fr › Composés chimiques organiques › Hydrocarbures › Hydrocarbures cycliques › Hydrocarbures alicycliques › Cyclopentanes › Deneddylation of ribosomal proteins promotes...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines ribosomiques › Deneddylation of ribosomal proteins promotes...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Mort cellulaire › Mort cellulaire régulée › Apoptose › Deneddylation of ribosomal proteins promotes...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Ubiquitines › Protéine NEDD8 › Deneddylation of ribosomal proteins promotes...