Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression.
ATPases Associated with Diverse Cellular Activities
/ genetics
Animals
Bortezomib
/ pharmacology
Cell Line, Tumor
Female
Gene Editing
Gene Expression Regulation
Gene Knockout Techniques
HEK293 Cells
Humans
Mice, Inbred BALB C
Mice, Inbred C57BL
Multiple Myeloma
Neoplastic Processes
Phosphorylation
Proteasome Endopeptidase Complex
/ genetics
Proteasome Inhibitors
/ pharmacology
Protein Serine-Threonine Kinases
/ genetics
Protein-Tyrosine Kinases
/ genetics
TYK2 Kinase
/ metabolism
Triple Negative Breast Neoplasms
/ metabolism
Dyrk Kinases
DYRK
kinase inhibitor
multiple myeloma
proteasome inhibitor
triple-negative breast cancer
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
03 12 2019
03 12 2019
Historique:
pubmed:
23
11
2019
medline:
2
4
2020
entrez:
23
11
2019
Statut:
ppublish
Résumé
Dependence on the 26S proteasome is an Achilles' heel for triple-negative breast cancer (TNBC) and multiple myeloma (MM). The therapeutic proteasome inhibitor, bortezomib, successfully targets MM but often leads to drug-resistant disease relapse and fails in breast cancer. Here we show that a 26S proteasome-regulating kinase, DYRK2, is a therapeutic target for both MM and TNBC. Genome editing or small-molecule mediated inhibition of DYRK2 significantly reduces 26S proteasome activity, bypasses bortezomib resistance, and dramatically delays in vivo tumor growth in MM and TNBC thereby promoting survival. We further characterized the ability of LDN192960, a potent and selective DYRK2-inhibitor, to alleviate tumor burden in vivo. The drug docks into the active site of DYRK2 and partially inhibits all 3 core peptidase activities of the proteasome. Our results suggest that targeting 26S proteasome regulators will pave the way for therapeutic strategies in MM and TNBC.
Identifiants
pubmed: 31754034
pii: 1912033116
doi: 10.1073/pnas.1912033116
pmc: PMC6900511
doi:
Substances chimiques
Proteasome Inhibitors
0
Bortezomib
69G8BD63PP
Protein-Tyrosine Kinases
EC 2.7.10.1
TYK2 Kinase
EC 2.7.10.2
Protein Serine-Threonine Kinases
EC 2.7.11.1
PSMB5 protein, human
EC 3.4.25.1
PSMC4 protein, human
EC 3.4.25.1
Proteasome Endopeptidase Complex
EC 3.4.25.1
ATP dependent 26S protease
EC 3.4.99.-
ATPases Associated with Diverse Cellular Activities
EC 3.6.4.-
Banques de données
PDB
['6K0J']
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
24881-24891Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM074024
Pays : United States
Organisme : NLM NIH HHS
ID : T15 LM011271
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA194107
Pays : United States
Organisme : Cancer Research UK
ID : C52419/A22869
Pays : United Kingdom
Informations de copyright
Copyright © 2019 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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