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

Arthur Aubry; Joel D Pearson; Jason Charish; Tao Yu; Jeremy M Sivak; Dimitris P Xirodimas; Hervé Avet-Loiseau; Jill Corre; Philippe P Monnier; Rod Bremner

doi:10.1016/j.celrep.2023.112925

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

Cell Rep. 2023 Aug 29;42(8):112925. doi: 10.1016/j.celrep.2023.112925. Epub 2023 Aug 7.

Authors

Affiliations

¹ 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.
² Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada.
³ 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.
⁴ 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.
⁵ CRBM, University Montpellier, CNRS, Montpellier, France.
⁶ 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.
⁷ 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.

PMID: 37552601
DOI: 10.1016/j.celrep.2023.112925

Abstract

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.

Keywords: CP: Cancer; MYCN; RPL11; melphalan; multiple myeloma; nucleoli; p53; pevonedistat; retinoblastoma; synergy; topotecan.

Publication types

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

MeSH terms

Apoptosis
Cell Line, Tumor
Cyclopentanes / pharmacology
NEDD8 Protein
Ribosomal Proteins
Topotecan*
Tumor Suppressor Protein p53*
bcl-2-Associated X Protein

Substances

pevonedistat
Topotecan
Tumor Suppressor Protein p53
bcl-2-Associated X Protein
Cyclopentanes
Ribosomal Proteins
NEDD8 Protein

Grants and funding

173474/CIHR/Canada