Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with reported incidences of ~800 000 cases each year. One of the critical determinants in patient response to radiotherapy, particularly for oropharyngeal cancers, is human papillomavirus (HPV) status where HPV-positive patients display improved survival rates and outcomes particularly because of increased responsiveness to radiotherapy. The increased radiosensitivity of HPV-positive HNSCC has been largely linked with defects in the signalling and repair of DNA double-strand breaks. Therefore, strategies to further radiosensitise HPV-positive HNSCC, but also radioresistant HPV-negative HNSCC, have focussed on targeting key DNA repair proteins including PARP, DNA-Pk, ATM and ATR. However, inhibitors against CHK1 and WEE1 involved in cell-cycle checkpoint activation have also been investigated as targets for radiosensitisation in HNSCC. These studies, largely conducted using established HNSCC cell lines in vitro, have demonstrated variability in the response dependent on the specific inhibitors and cell models utilised. However, promising results are evident targeting specifically PARP, DNA-Pk, ATR and CHK1 in synergising with radiation in HNSCC cell killing. Nevertheless, these preclinical studies require further expansion and investigation for translational opportunities for the effective treatment of HNSCC in combination with radiotherapy.

中文翻译：

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HPV 阳性和 HPV 阴性头颈鳞状细胞癌的放射生物学

头颈鳞状细胞癌 (HNSCC) 是全球第六大常见癌症，每年报告的发病率约为 80 万例。患者对放疗（尤其是口咽癌）反应的关键决定因素之一是人乳头瘤病毒 (HPV) 状态，其中 HPV 阳性患者的生存率和结果有所改善，特别是因为对放疗的反应增加。HPV 阳性 HNSCC 放射敏感性的增加在很大程度上与 DNA 双链断裂的信号传导和修复缺陷有关。因此，进一步提高 HPV 阳性 HNSCC 放射敏感性以及放射抗性 HPV 阴性 HNSCC 的策略重点关注关键 DNA 修复蛋白，包括 PARP、DNA-Pk、ATM 和 ATR。然而，参与细胞周期检查点激活的 CHK1 和 WEE1 抑制剂也被研究作为 HNSCC 放射增敏的靶点。这些研究主要使用体外建立的 HNSCC 细胞系进行，已证明反应的可变性取决于所使用的特定抑制剂和细胞模型。然而，特异性针对 PARP、DNA-Pk、ATR 和 CHK1 与放射协同杀死 HNSCC 细胞的效果明显有希望。然而，这些临床前研究需要进一步扩展和调查，寻找联合放疗有效治疗 HNSCC 的转化机会。