Head and neck squamous cell carcinoma (HNSCC) is a challenging cancer with little change in five-year overall survival rate of 50–60% over the last two decades. Radiation with or without platinum-based drugs remains the standard of care despite limited benefit and high toxicity. HNSCCs often overexpress epidermal growth factor receptor (EGFR) and inhibition of EGFR signaling enhances radiation sensitivity by interfering with repair of radiation-induced DNA breaks. Poly (adenosine diphosphate-ribose) polymerase-1 (PARP1) also participates in DNA damage repair, but its inhibition provides benefit in cancers that lack DNA repair by homologous recombination (HR) such as BRCA-mutant breast cancer. HNSCCs in contrast are typically BRCA wild-type and proficient in HR repair, making it challenging to apply anti-PARP1 therapy in this model. A recently published study showed that a combination of EGFR and PARP1 inhibition induced more DNA damage and greater growth control than each single agent in HNSCC cells. This led us to hypothesize that a combination of EGFR and PARP1 inhibition would enhance the efficacy of radiation to a greater extent than each single agent, providing a rationale for paradigm-shifting combinatorial approaches to improve the standard of care in HNSCC. Here, we report a proof-of-concept study using Detroit562 HNSCC cells, which are proficient for DNA repair by both HR and non-homologous end joining (NHEJ) mechanisms. We tested the effect of adding cetuximab and/or olaparib (inhibitors of EGFR and PARP1, respectively) to radiation and compared it to that of cisplatin and radiation combination, which is the standard of care. Our results demonstrate that the combination of cetuximab and olaparib with radiation was superior to the combination of any single drug with radiation in terms of induction of unrepaired DNA damage, induction of senescence, apoptosis and clonogenic death, and tumor growth control in mouse xenografts. Combined with our recently published phase I safety data on cetuximab/olaparib/radiation triple combination, the data reported here demonstrate a potential for combining biologically-based therapies that might optimize radiosensitization in HNSCC.

头颈部鳞状细胞癌 (HNSCC) 是一种具有挑战性的癌症，过去 20 年中 50-60% 的五年总生存率几乎没有变化。尽管获益有限且毒性高，但有或没有铂类药物的放射仍然是标准的治疗方法。HNSCC 通常过度表达表皮生长因子受体 (EGFR)，抑制 EGFR 信号通过干扰辐射诱导的 DNA 断裂的修复来增强辐射敏感性。聚（二磷酸腺苷-核糖）聚合酶-1 (PARP1) 也参与 DNA 损伤修复，但它的抑制作用对缺乏通过同源重组 (HR) 进行 DNA 修复的癌症（如 BRCA 突变型乳腺癌）有益。相比之下，HNSCC 通常是 BRCA 野生型，并且擅长 HR 修复，因此在该模型中应用抗 PARP1 疗法具有挑战性。最近发表的一项研究表明，在 HNSCC 细胞中，EGFR 和 PARP1 抑制的组合比每种单一药物诱导更多的 DNA 损伤和更大的生长控制。这使我们假设 EGFR 和 PARP1 抑制的组合将在更大程度上提高放疗的疗效，这为改变范式的组合方法提供了理论依据，以提高 HNSCC 的护理标准。在这里，我们报告了一项使用 Detroit562 HNSCC 细胞的概念验证研究，这些细胞通过 HR 和非同源末端连接 (NHEJ) 机制精通 DNA 修复。我们测试了在放疗中加入西妥昔单抗和/或奥拉帕尼（分别是 EGFR 和 PARP1 抑制剂）的效果，并将其与作为护理标准的顺铂和放疗组合的效果进行了比较。我们的结果表明，在诱导未修复的 DNA 损伤、诱导衰老、细胞凋亡和克隆性死亡以及小鼠异种移植物中的肿瘤生长控制方面，西妥昔单抗和奥拉帕尼与辐射的组合优于任何单一药物与辐射的组合。结合我们最近发表的关于西妥昔单抗/奥拉帕利/放疗三联疗法的 I 期安全数据，这里报告的数据证明了结合基于生物学的疗法的潜力，这些疗法可能优化 HNSCC 的放射增敏作用。