Department of Otolaryngology, University of California, San Francisco, CA, USA.
Departments of Radiation Oncology and Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
Oral Oncol. 2019 Aug;95:35-42. doi: 10.1016/j.oraloncology.2019.05.028. Epub 2019 Jun 6.
Cisplatin is commonly used in the treatment of head and neck squamous cell carcinoma (HNSCC), and the repair of cisplatin-induced DNA damage involves activation of the DNA damage response protein ataxia telangiectasia and Rad3-related (ATR). Resistance to cisplatin therapy exacerbates adverse toxicities and is associated with poor outcomes. Since repair of cisplatin-induced DNA damage contributes to resistance, we hypothesized that inhibition of ATR using AZD6738, a well-tolerated and orally-bioavailable inhibitor, would enhance the sensitivity of HNSCC cells and tumors to cisplatin.
A panel of human papilloma virus-negative (HPV) and HPV HNSCC cell lines were treated with cisplatin in the absence or presence of AZD6738, and effects on cell viability, colony formation, apoptosis signaling, and DNA damage were assessed. The impact of co-treatment with cisplatin plus AZD6738 on the growth of HPV and HPV cell line- and patient-derived xenograft tumors was also examined.
Inhibition of ATR with AZD6738 enhanced cisplatin-induced growth inhibition of HNSCC cell lines and tumors, in association with increased apoptosis signaling and DNA damage. Both HPV and HPV models were sensitized to cisplatin by ATR inhibition.
Inhibition of ATR promotes sensitization to cisplatin in preclinical in vitro and in vivo models of HPV and HVP HNSCC, supporting clinical evaluation of this strategy in this disease.
顺铂常用于治疗头颈部鳞状细胞癌（HNSCC），而顺铂诱导的 DNA 损伤的修复涉及到共济失调毛细血管扩张症和 Rad3 相关蛋白（ATR）的 DNA 损伤反应蛋白的激活。对顺铂治疗的耐药性加剧了不良反应，并与不良预后相关。由于修复顺铂诱导的 DNA 损伤有助于耐药性，我们假设使用 AZD6738（一种耐受性良好且可口服的抑制剂）抑制 ATR 会增强 HNSCC 细胞和肿瘤对顺铂的敏感性。
用顺铂处理一组人乳头瘤病毒阴性（HPV）和 HPV HNSCC 细胞系，在不存在或存在 AZD6738 的情况下，评估对细胞活力、集落形成、细胞凋亡信号和 DNA 损伤的影响。还研究了顺铂加 AZD6738 联合治疗对 HPV 和 HPV 细胞系和患者来源异种移植肿瘤生长的影响。
用 AZD6738 抑制 ATR 增强了 HNSCC 细胞系和肿瘤对顺铂诱导的生长抑制作用，同时增加了细胞凋亡信号和 DNA 损伤。HPV 和 HPV 模型均通过 ATR 抑制对顺铂敏感。
ATR 抑制在 HPV 和 HPV HNSCC 的临床前体外和体内模型中促进了对顺铂的敏感性，支持在该疾病中对此策略的临床评估。
