Heemskerk Tim, van de Kamp Gerarda, Rovituso Marta, Kanaar Roland, Essers Jeroen
Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands (the).
R&D Department, HollandPTC, Delft, Netherlands (the).
Clin Transl Radiat Oncol. 2024 Dec 4;51:100898. doi: 10.1016/j.ctro.2024.100898. eCollection 2025 Mar.
Radiotherapy induces tumor cell killing by generating DNA double strand breaks (DSBs). The effectiveness of radiotherapy is significantly influenced by the repair of DSBs, which counteracts this lethal effect. Current investigations are focused on determining whether non-homologous end joining (NHEJ) or homologous recombination is the predominant repair pathway following proton and photon radiation.
In this study, we examined the response of FaDu cells, a head and neck squamous cell carcinoma model, to spread-out Bragg peak (SOBP) proton and photon radiation combined with mild hyperthermia (42 °C for one hour) to induce homologous recombination deficiency or NHEJ inhibition by AZD7648.
Hyperthermia resulted in stronger radiosensitization after proton radiation (SR = 1.53) compared to photon radiation (SR = 1.32). Conversely, NHEJ inhibition did not produce a significant differential effect between photon and proton radiation. This indicates a greater reliance on homologous recombination following proton radiation compared to photon radiation. We found that the number of DSBs formed after photon versus proton irradiation is comparable. Interestingly, the homologous recombination protein Rad51 accumulated more frequently at DSBs following proton irradiation than photon irradiation.
These findings support the hypothesis that cells rely more on homologous recombination to repair proton-induced DNA damage compared to photon-induced DNA damage. As clinically applied hyperthermia enhances the therapeutic effect of photon irradiation by, among other factors, inducing homologous recombination deficiency, our results suggests that hyperthermia could be more effective in combination with proton irradiation than photon irradiation.
放射治疗通过产生DNA双链断裂（DSB）来诱导肿瘤细胞死亡。DSB的修复会抵消这种致死效应，从而显著影响放射治疗的效果。目前的研究集中在确定质子和光子辐射后，非同源末端连接（NHEJ）或同源重组是否为主要的修复途径。
在本研究中，我们检测了头颈部鳞状细胞癌模型FaDu细胞对扩展布拉格峰（SOBP）质子和光子辐射联合轻度热疗（42℃ 1小时）的反应，以通过AZD7648诱导同源重组缺陷或NHEJ抑制。
与光子辐射（增敏比SR = 1.32）相比，热疗在质子辐射后产生更强的放射增敏作用（SR = 1.53）。相反，NHEJ抑制在光子和质子辐射之间未产生显著的差异效应。这表明与光子辐射相比，质子辐射后细胞对同源重组的依赖性更强。我们发现光子照射与质子照射后形成的DSB数量相当。有趣的是，与光子照射后相比，质子照射后同源重组蛋白Rad51在DSB处更频繁地积累。
这些发现支持以下假设：与光子诱导的DNA损伤相比，细胞在修复质子诱导的DNA损伤时更依赖同源重组。由于临床应用的热疗通过诱导同源重组缺陷等因素增强了光子照射的治疗效果，我们的结果表明热疗与质子照射联合使用可能比与光子照射联合使用更有效。
