Effect of ATR Inhibition in RT Response of HPV-Negative and HPV-Positive Head and Neck Cancers
Open Access
- 3 February 2021
- journal article
- research article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 22 (4), 1504
- https://doi.org/10.3390/ijms22041504
Abstract
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.Funding Information
- Fonds Wetenschappelijk Onderzoek (G0A4116N)
- Emmanuel van der Schueren fellowship for postdoctoral researchers from Kom op Tegen Kanker (Emmanuel van der Schueren fellowship for postdoctoral researchers)
- Kom op tegen Kanker (project grant)
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