Cancer Research Centre, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, 200 London Road, LiverpoolL3 9TA, UK.
Expert Rev Mol Med. 2020 Jul 2;22:e3. doi: 10.1017/erm.2020.4.
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.
头颈部鳞状细胞癌（HNSCC）是全球第六大常见癌症，每年报告的发病率约为 80 万例。在患者对放疗的反应中，一个关键决定因素是人类乳头状瘤病毒（HPV）状态，HPV 阳性患者的生存率和预后更好，这主要是因为对放疗的反应性增加。HPV 阳性 HNSCC 的放射敏感性增加，在很大程度上与 DNA 双链断裂的信号转导和修复缺陷有关。因此，进一步增强 HPV 阳性 HNSCC 的放射敏感性，以及对 HPV 阴性 HNSCC 的放射抗性的策略，集中在针对关键的 DNA 修复蛋白，包括 PARP、DNA-Pk、ATM 和 ATR。然而，针对细胞周期检查点激活中涉及 CHK1 和 WEE1 的抑制剂也被研究作为 HNSCC 放射增敏的靶点。这些研究主要在体外使用已建立的 HNSCC 细胞系进行，结果表明，由于使用的特定抑制剂和细胞模型的不同，反应存在差异。然而，在 HNSCC 细胞杀伤中，PARP、DNA-Pk、ATR 和 CHK1 的特异性靶向与放疗协同作用，显示出有希望的结果。然而，这些临床前研究需要进一步扩展和研究，以寻找有效的治疗 HNSCC 与放疗相结合的转化机会。
