The limitations of targeting MEK signalling in Glioblastoma therapy.
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Apoptosis
Brain Neoplasms
/ therapy
Cell Adhesion
Cell Death
Cell Line, Tumor
Cell Proliferation
/ drug effects
Chorioallantoic Membrane
/ metabolism
Drug Screening Assays, Antitumor
Glioblastoma
/ therapy
Humans
MAP Kinase Kinase 1
/ antagonists & inhibitors
Neoplasm Invasiveness
Neoplasm Metastasis
Phosphatidylinositol 3-Kinases
/ metabolism
Phosphorylation
Pyridones
/ pharmacology
Pyrimidinones
/ pharmacology
Signal Transduction
Temozolomide
/ pharmacology
Translational Research, Biomedical
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
04 05 2020
04 05 2020
Historique:
received:
08
08
2019
accepted:
15
04
2020
entrez:
6
5
2020
pubmed:
6
5
2020
medline:
7
1
2021
Statut:
epublish
Résumé
Glioblastoma (GB) is a highly aggressive, difficult to treat brain tumour. Successful treatment, consisting of maximal safe tumour de-bulking, followed by radiotherapy and treatment with the alkylating agent Temozolomide (TMZ), can extend patient survival to approximately 15 months. Combination treatments based on the inhibition of the PI3K pathway, which is the most frequently activated signalling cascade in GB, have so far only shown limited therapeutic success. Here, we use the clinically approved MEK inhibitor Trametinib to investigate its potential use in managing GB. Trametinib has a strong anti-proliferative effect on established GB cell lines, stem cell-like cells and their differentiated progeny and while it does not enhance anti-proliferative and cell death-inducing properties of the standard treatment, i.e. exposure to radiation or TMZ, neither does MEK inhibition block their effectiveness. However, upon MEK inhibition some cell populations appear to favour cell-substrate interactions in a sprouting assay and become more invasive in the Chorioallantoic Membrane assay, which assesses cell penetration into an organic membrane. While this increased invasion can be modulated by additional inhibition of the PI3K signalling cascade, there is no apparent benefit of blocking MEK compared to targeting PI3K.
Identifiants
pubmed: 32366879
doi: 10.1038/s41598-020-64289-6
pii: 10.1038/s41598-020-64289-6
pmc: PMC7198577
doi:
Substances chimiques
Pyridones
0
Pyrimidinones
0
trametinib
33E86K87QN
MAP Kinase Kinase 1
EC 2.7.12.2
Temozolomide
YF1K15M17Y
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7401Références
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