Effect of ATR Inhibition in RT Response of HPV-Negative and HPV-Positive Head and Neck Cancers

International Journal of Molecular Sciences

Mary Glorieux¹  Rüveyda Dok¹  Marieke Bamps¹  Sandra Nuyts¹ 

[1] Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven, University of Leuven, 3000 Leuven, Belgium;

关键词: head and neck cancers;    human papillomavirus;    DNA damage response;    radiotherapy;    ATR inhibition;   

DOI  :  10.3390/ijms22041504

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown