Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer.
Animals
Cell Line, Tumor
Colorectal Neoplasms
/ drug therapy
Cyclopentanes
/ pharmacology
DNA Mismatch Repair
Endometrial Neoplasms
/ drug therapy
Female
HCT116 Cells
Humans
Immunotherapy
/ methods
Mice, Inbred C57BL
Mice, Transgenic
Microsatellite Instability
Mutation
NEDD8 Protein
/ antagonists & inhibitors
Programmed Cell Death 1 Receptor
/ antagonists & inhibitors
Protein Stability
Proteome
/ genetics
Pyrimidines
/ pharmacology
Xenograft Model Antitumor Assays
colorectal cancer (COAD)
endometrial cancer (UCEC)
immunotherapy
microsatellite instability (MSI)
mismatch repair (MMR)
neddylation
protein degredation
protein homeostasis
Journal
Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617
Informations de publication
Date de publication:
16 03 2020
16 03 2020
Historique:
received:
31
01
2019
revised:
22
11
2019
accepted:
30
01
2020
pubmed:
29
2
2020
medline:
11
8
2020
entrez:
29
2
2020
Statut:
ppublish
Résumé
Deficient DNA mismatch repair (dMMR) induces a hypermutator phenotype that can lead to tumorigenesis; however, the functional impact of the high mutation burden resulting from this phenotype remains poorly explored. Here, we demonstrate that dMMR-induced destabilizing mutations lead to proteome instability in dMMR tumors, resulting in an abundance of misfolded protein aggregates. To compensate, dMMR cells utilize a Nedd8-mediated degradation pathway to facilitate clearance of misfolded proteins. Blockade of this Nedd8 clearance pathway with MLN4924 causes accumulation of misfolded protein aggregates, ultimately inducing immunogenic cell death in dMMR cancer cells. To leverage this immunogenic cell death, we combined MLN4924 treatment with PD1 inhibition and found the combination was synergistic, significantly improving efficacy over either treatment alone.
Identifiants
pubmed: 32109374
pii: S1535-6108(20)30050-7
doi: 10.1016/j.ccell.2020.01.011
pmc: PMC7337255
mid: NIHMS1568888
pii:
doi:
Substances chimiques
Cyclopentanes
0
NEDD8 Protein
0
NEDD8 protein, human
0
PDCD1 protein, human
0
Programmed Cell Death 1 Receptor
0
Proteome
0
Pyrimidines
0
pevonedistat
S3AZD8D215
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
371-386.e12Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA216103
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA218287
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA098258
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA217842
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests G.B.M. consults with AstraZeneca, ImmunoMET, Ionis, Nuevolution, PDX bio, Signalchem, Symphogen, and Tarveda, has stock options with Catena Pharmaceuticals, ImmunoMet, SignalChem, Spindle Top Ventures, and Tarveda, sponsored research from AstraZeneca, Immunomet, Pfizer, Nanostring, and Tesaro, travel support from Chrysallis Bio, and has licensed technology to Nanostring and Myriad Genetics. The other authors declare no competing interests.
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