Zhou Chumin, Fabbrizi Maria Rita, Hughes Jonathan R, Grundy Gabrielle J, Parsons Jason L
Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
Clatterbridge Cancer Centre NHS Foundation Trust, Bebington, United Kingdom.
Front Oncol. 2022 Aug 16;12:940377. doi: 10.3389/fonc.2022.940377. eCollection 2022.
A critical risk factor for head and neck squamous cell carcinoma (HNSCC), particularly of the oropharynx, and the response to radiotherapy is human papillomavirus (HPV) type-16/18 infection. Specifically, HPV-positive HNSCC display increased radiosensitivity and improved outcomes, which has been linked with defective signalling and repair of DNA double-strand breaks (DSBs). This differential response to radiotherapy has been recapitulated using cell lines, although studies utilising appropriate 3D models that are more reflective of the original tumour are scarce. Furthermore, strategies to enhance the sensitivity of relatively radioresistant HPV-negative HNSCC to radiotherapy are still required. We have analysed the comparative response of 3D spheroid models of oropharyngeal squamous cell carcinoma to x-ray (photon) irradiation and provide further evidence that HPV-positive cells, in this case now grown as spheroids, show greater inherent radiosensitivity compared to HPV-negative spheroids due to defective DSB repair. We subsequently analysed these and an expanded number of spheroid models, with a particular focus on relatively radioresistant HPV-negative HNSCC, for impact of poly(ADP-ribose) polymerase (PARP) inhibitors (olaparib and talazoparib) in significantly inhibiting spheroid growth in response to photons but also proton beam therapy. We demonstrate that in general, PARP inhibition can further radiosensitise particularly HPV-negative HNSCC spheroids to photons and protons leading to significant growth suppression. The degree of enhanced radiosensitivity was observed to be dependent on the model and on the tumour site (oropharynx, larynx, salivary gland, or hypopharynx) from which the cells were derived. We also provide evidence suggesting that PARP inhibitor effectiveness relates to homologous recombination repair proficiency. Interestingly though, we observed significantly enhanced effectiveness of talazoparib versus olaparib specifically in response to proton irradiation. Nevertheless, our data generally support that PARP inhibition in combination with radiotherapy (photons and protons) should be considered further as an effective treatment for HNSCC, particularly for relatively radioresistant HPV-negative tumours.
头颈部鳞状细胞癌（HNSCC），尤其是口咽癌的一个关键风险因素以及对放疗的反应是16/18型人乳头瘤病毒（HPV）感染。具体而言，HPV阳性的HNSCC表现出更高的放射敏感性和更好的预后，这与DNA双链断裂（DSB）的信号传导缺陷和修复有关。尽管利用更能反映原始肿瘤的合适三维模型的研究很少，但使用细胞系已经重现了这种对放疗的差异反应。此外，仍需要提高相对放射抗性的HPV阴性HNSCC对放疗敏感性的策略。我们分析了口咽鳞状细胞癌的三维球体模型对X射线（光子）照射的比较反应，并提供了进一步的证据，即HPV阳性细胞（在这种情况下以球体形式生长）由于DSB修复缺陷，与HPV阴性球体相比显示出更高的固有放射敏感性。我们随后分析了这些以及更多数量的球体模型，特别关注相对放射抗性的HPV阴性HNSCC，研究聚（ADP - 核糖）聚合酶（PARP）抑制剂（奥拉帕利和他拉唑帕利）在显著抑制球体对光子以及质子束治疗的生长方面的影响。我们证明，一般来说，PARP抑制可以进一步使尤其是HPV阴性的HNSCC球体对光子和质子放射增敏，导致显著的生长抑制。观察到放射增敏程度取决于模型以及细胞来源的肿瘤部位（口咽、喉、唾液腺或下咽）。我们还提供证据表明PARP抑制剂的有效性与同源重组修复能力有关。然而有趣的是，我们观察到他拉唑帕利相对于奥拉帕利在对质子照射的反应中有效性显著增强。尽管如此，我们的数据总体上支持，PARP抑制联合放疗（光子和质子）应进一步被视为HNSCC的有效治疗方法，特别是对于相对放射抗性的HPV阴性肿瘤。
