MEK inhibition reduced vascular tumor growth and coagulopathy in a mouse model with hyperactive GNAQ.
Animals
Mice
GTP-Binding Protein alpha Subunits
/ metabolism
GTP-Binding Protein alpha Subunits, Gq-G11
/ genetics
Vascular Neoplasms
Endothelial Cells
/ metabolism
Apoptosis
Melanoma
/ genetics
Uveal Neoplasms
/ genetics
Mutation
Disease Models, Animal
Mitogen-Activated Protein Kinase Kinases
/ metabolism
Cell Line, Tumor
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
06 04 2023
06 04 2023
Historique:
received:
17
11
2021
accepted:
21
03
2023
medline:
10
4
2023
entrez:
6
4
2023
pubmed:
7
4
2023
Statut:
epublish
Résumé
Activating non-inherited mutations in the guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) gene family have been identified in childhood vascular tumors. Patients experience extensive disfigurement, chronic pain and severe complications including a potentially lethal coagulopathy termed Kasabach-Merritt phenomenon. Animal models for this class of vascular tumors do not exist. This has severely hindered the discovery of the molecular consequences of GNAQ mutations in the vasculature and, in turn, the preclinical development of effective targeted therapies. Here we report a mouse model expressing hyperactive mutant GNAQ in endothelial cells. Mutant mice develop vascular and coagulopathy phenotypes similar to those seen in patients. Mechanistically, by transcriptomic analysis we demonstrate increased mitogen activated protein kinase signaling in the mutant endothelial cells. Targeting of this pathway with Trametinib suppresses the tumor growth by reducing vascular cell proliferation and permeability. Trametinib also prevents the development of coagulopathy and improves mouse survival.
Identifiants
pubmed: 37024491
doi: 10.1038/s41467-023-37516-7
pii: 10.1038/s41467-023-37516-7
pmc: PMC10079932
doi:
Substances chimiques
GTP-Binding Protein alpha Subunits
0
GTP-Binding Protein alpha Subunits, Gq-G11
EC 3.6.5.1
Mitogen-Activated Protein Kinase Kinases
EC 2.7.12.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1929Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL117952
Pays : United States
Organisme : NIH HHS
ID : S10 OD025045
Pays : United States
Organisme : NIDDK NIH HHS
ID : U54 DK126108
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001425
Pays : United States
Informations de copyright
© 2023. The Author(s).
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