Effect of ATR Inhibition in RT Response of HPV-Negative and HPV-Positive Head and Neck Cancers.
Animals
Ataxia Telangiectasia Mutated Proteins
/ antagonists & inhibitors
Cell Line, Tumor
DNA Repair
Female
Head and Neck Neoplasms
/ complications
Humans
Indoles
Mice
Mice, Nude
Morpholines
Papillomavirus Infections
/ complications
Photochemotherapy
Pyrimidines
/ pharmacology
Radiation-Sensitizing Agents
/ pharmacology
Squamous Cell Carcinoma of Head and Neck
/ complications
Sulfonamides
Sulfoxides
/ pharmacology
Xenograft Model Antitumor Assays
ATR inhibition
DNA damage response
head and neck cancers
human papillomavirus
radiotherapy
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
03 Feb 2021
03 Feb 2021
Historique:
received:
24
12
2020
revised:
21
01
2021
accepted:
28
01
2021
entrez:
6
2
2021
pubmed:
7
2
2021
medline:
21
4
2021
Statut:
epublish
Résumé
Radiotherapy (RT) has a central role in head and neck squamous cell carcinoma (HNSCC) treatment. Targeted therapies modulating DNA damage response (DDR) and more specific cell cycle checkpoints can improve the radiotherapeutic response. Here, we assessed the influence of ataxia-telangiectasia mutated and Rad3-related (ATR) inhibition with the ATR inhibitor AZD6738 on RT response in both human papillomavirus (HPV)-negative and HPV-positive HNSCC. We found that ATR inhibition enhanced RT response in HPV-negative and HPV-positive cell lines independent of HPV status. The radiosensitizing effect of AZD6738 was correlated with checkpoint kinase 1 (CHK1)-mediated abrogation of G2/M-arrest. This resulted in the inhibition of RT-induced DNA repair and in an increase in the percentage of micronucleated cells. We validated the enhanced RT response in HPV-negative and HPV-positive xenograft models. These data demonstrate the potential use of ATR inhibition in combination with RT as a treatment option for both HPV-negative and HPV-positive HNSCC patients.
Identifiants
pubmed: 33546122
pii: ijms22041504
doi: 10.3390/ijms22041504
pmc: PMC7913134
pii:
doi:
Substances chimiques
Indoles
0
Morpholines
0
Pyrimidines
0
Radiation-Sensitizing Agents
0
Sulfonamides
0
Sulfoxides
0
ceralasertib
85RE35306Z
ATR protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Fonds Wetenschappelijk Onderzoek
ID : G0A4116N
Organisme : Emmanuel van der Schueren fellowship for postdoctoral researchers from Kom op Tegen Kanker
ID : Emmanuel van der Schueren fellowship for postdoctoral researchers
Organisme : Kom op Tegen Kanker
ID : project grant
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