An oncogenic splice variant of PDGFRα in adult glioblastoma as a therapeutic target for selective CDK4/6 inhibitors.
Cyclin D1
/ metabolism
Cyclin-Dependent Kinase 4
/ antagonists & inhibitors
Cyclin-Dependent Kinase 6
/ antagonists & inhibitors
Gene Editing
Glioblastoma
/ drug therapy
HEK293 Cells
Humans
Molecular Targeted Therapy
RNA Splice Sites
Receptor, Platelet-Derived Growth Factor alpha
/ genetics
Signal Transduction
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
24 01 2022
24 01 2022
Historique:
received:
14
03
2021
accepted:
06
01
2022
entrez:
25
1
2022
pubmed:
26
1
2022
medline:
9
3
2022
Statut:
epublish
Résumé
Understanding human genome alterations is necessary to optimize genome-based cancer therapeutics. However, some newly discovered mutations remain as variants of unknown significance (VUS). Here, the mutation c.1403A > G in exon 10 of the platelet-derived growth factor receptor-alpha (PDGFRA) gene, a VUS found in adult glioblastoma multiforme (GBM), was introduced in human embryonal kidney 293 T (HEK293T) cells using genome editing to investigate its potential oncogenic functions. Genome editing was performed using CRISPR/Cas9; the proliferation, drug sensitivity, and carcinogenic potential of genome-edited cells were investigated. We also investigated the mechanism underlying the observed phenotypes. Three GBM patients carrying the c.1403A > G mutation were studied to validate the in vitro results. The c.1403A > G mutation led to a splice variant (p.K455_N468delinsN) because of the generation of a 3'-acceptor splice site in exon 10. PDGFRA-mutated HEK293T cells exhibited a higher proliferative activity via PDGFRα and the cyclin-dependent kinase (CDK)4/CDK6-cyclin D1 signaling pathway in a ligand-independent manner. They showed higher sensitivity to multi-kinase, receptor tyrosine kinase, and CDK4/CDK6 inhibitors. Of the three GBM patients studied, two harbored the p.K455_N468delinsN splice variant. The splicing mutation c.1403A > G in PDGFRA is oncogenic in nature. Kinase inhibitors targeting PDGFRα and CDK4/CDK6 signaling should be evaluated for treating GBM patients harboring this mutation.
Identifiants
pubmed: 35075231
doi: 10.1038/s41598-022-05391-9
pii: 10.1038/s41598-022-05391-9
pmc: PMC8786844
doi:
Substances chimiques
CCND1 protein, human
0
RNA Splice Sites
0
Cyclin D1
136601-57-5
Receptor, Platelet-Derived Growth Factor alpha
EC 2.7.10.1
CDK4 protein, human
EC 2.7.11.22
CDK6 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinase 4
EC 2.7.11.22
Cyclin-Dependent Kinase 6
EC 2.7.11.22
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1275Informations de copyright
© 2022. The Author(s).
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