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

Rüveyda Dok,Marieke Bamps,Mary Glorieux,Sandra Nuyts

doi: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.

Highlights

Head and neck squamous cell carcinoma (HNSCC) are subdivided in human papillomavirus (HPV)-positive and HPV-negative HNSCC
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
The administration of AZD6738 in combination with RT resulted in decreased clonogenic cell survival in both HPV-negative and HPV-positive HNSCC cell lines (Figure 2)

Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC) are subdivided in human papillomavirus (HPV)-positive and HPV-negative HNSCC. The latter is most often associated with alcohol and tobacco use [1,2]. Despite considerable technological advances in RT and new insights in the biological interaction between RT and the tumor, many HNSCC patients experience local tumor recurrences. This is especially the case for the HPV-negative group of HNSCC patients, highlighting the differential response to RT between the two groups of HNSCC [1,2,3]. One of the similarities was the importance of cell cycle-related genes in the RT response of HNSCC cells [6]

Methods

Results

Conclusion