SUMO pathway inhibition targets an aggressive pancreatic cancer subtype.
Aged
Animals
Apoptosis
Carcinoma, Pancreatic Ductal
/ drug therapy
Cell Line, Tumor
Cell Proliferation
Enzyme Inhibitors
/ pharmacology
Esters
/ pharmacology
Female
Gene Amplification
Gene Expression
Humans
Male
Mice
Middle Aged
Neoplasm Transplantation
Organoids
/ metabolism
Pancreatic Neoplasms
/ drug therapy
Prognosis
Proto-Oncogene Proteins c-myc
/ genetics
Pyrazoles
/ pharmacology
Pyrimidines
/ pharmacology
SUMO-1 Protein
/ genetics
Small Ubiquitin-Related Modifier Proteins
/ genetics
Sulfonic Acids
Sumoylation
/ drug effects
Transcriptome
/ drug effects
Ubiquitin-Activating Enzymes
/ antagonists & inhibitors
Ubiquitin-Conjugating Enzymes
/ genetics
Ubiquitins
/ genetics
cancer
pancreatic cancer
Journal
Gut
ISSN: 1468-3288
Titre abrégé: Gut
Pays: England
ID NLM: 2985108R
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
02
11
2018
revised:
20
12
2019
accepted:
22
12
2019
pubmed:
1
2
2020
medline:
1
4
2021
entrez:
1
2
2020
Statut:
ppublish
Résumé
Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies. We analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC. We observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition. SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.
Identifiants
pubmed: 32001555
pii: gutjnl-2018-317856
doi: 10.1136/gutjnl-2018-317856
pmc: PMC7398468
doi:
Substances chimiques
Enzyme Inhibitors
0
Esters
0
ML-792
0
MYC protein, human
0
Myc protein, mouse
0
Proto-Oncogene Proteins c-myc
0
Pyrazoles
0
Pyrimidines
0
SUMO-1 Protein
0
SUMO1 protein, human
0
SUMO2 protein, human
0
SUMO3 protein, human
0
Small Ubiquitin-Related Modifier Proteins
0
Sulfonic Acids
0
Ubiquitins
0
Ubiquitin-Conjugating Enzymes
EC 2.3.2.23
SAE1 protein, human
EC 6.2.1.45
Ubiquitin-Activating Enzymes
EC 6.2.1.45
ubiquitin-conjugating enzyme UBC9
EC 6.3.2.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1472-1482Informations de copyright
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: SL is an employee of Takeda Pharmaceutical Company.
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