Pre-clinical activity of the oral DNA-PK inhibitor, peposertib (M3814), combined with radiation in xenograft models of cervical cancer.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
19 01 2022
19 01 2022
Historique:
received:
14
10
2021
accepted:
22
12
2021
entrez:
20
1
2022
pubmed:
21
1
2022
medline:
3
3
2022
Statut:
epublish
Résumé
DNA-dependent protein kinase (DNA-PK) plays a crucial role in repair of DNA double-strand breaks by facilitating non-homologous end-joining. Inhibitors of DNA-PK have the potential to block DNA repair and enhance DNA-damaging agents. Peposertib (M3814) is a DNA-PK inhibitor that has shown preclinical activity in combination with DNA-damaging agents, including ionizing radiation (IR) and topoisomerase II inhibitors. Here we evaluated the activity of peposertib (M3814) in combination with radiation in a mouse xenograft model of HPV-associated cervical cancer. Athymic nude female mice with established tumors derived from HeLa cells injected into the flank were treated with vehicle alone (n = 3), IR alone (n = 4), and peposertib (M38814) in combination with IR (M3814 + IR; n = 4). While IR alone was associated with a trend towards decreased tumor volume compared with untreated, only the M3814 + IR treatment arm was associated with consistent and significant reduction in tumor burden, which correlated with higher levels of γ-H2AX in tumor cells, a marker of double-strand DNA breaks. Our data support further clinical evaluation of the combination of peposertib (M38814) and IR in cervical cancer.
Identifiants
pubmed: 35046420
doi: 10.1038/s41598-021-04618-5
pii: 10.1038/s41598-021-04618-5
pmc: PMC8770623
doi:
Substances chimiques
Pyridazines
0
Quinazolines
0
DNA-Activated Protein Kinase
EC 2.7.11.1
peposertib
GN429E725A
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
974Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Informations de copyright
© 2022. The Author(s).
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