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
Affiliations
Arthur Aubry
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
Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada
Jason Charish
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
Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada
Jeremy M. Sivak
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
CRBM, University Montpellier, CNRS, Montpellier, France
Hervé Avet-Loiseau
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
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
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
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; Corresponding author
Summary: 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.
