Platinum-based chemoradiotherapy is a mainstay of organ-preserving therapy for patients with head and neck squamous cell carcinoma cancer (HNSCC). However, the disease eventually becomes resistant to treatment necessitating new therapies. Checkpoint kinase 1 and 2 (CHK1/2) are serine/threonine kinases that activate cell-cycle checkpoints and serve a critical role in the DNA-damage response (DDR). As resistance to cisplatin and radiation may involve a heightened DDR, we hypothesized that prexasertib, an inhibitor of CHK1/2, may enhance the cytotoxicity induced by cisplatin and irradiation in HNSCC. In this study, we found that combining prexasertib with cisplatin and radiation significantly decreased the in vitro survival fraction in HNSCC cell lines both with and without radiotherapy. Reduced survival was accompanied by inhibition of DNA repair checkpoint activation, which resulted in persistent DNA damage and increased apoptosis. In addition, NanoString analysis with the PanCancer Pathways Panel revealed that prexasertib downregulated NOTCH signaling target genes (NOTCH1, NOTCH2, and NOTCH3) and their associated ligands (JAG1, JAG2, SKP2, MAML2, and DLL1). Prexasertib also reduced NOTCH1, NOTCH3 and HES1 protein expression. Importantly, a significant tumor growth delay was observed in vivo in both human papillomavirus (HPV)-positive UM-SCC47 and HPV-negative UM-SCC1 cell line xenografts treated with prexasertib, cisplatin, and radiotherapy without increased toxicity as measured by mouse body weight. Taken together, prexasertib reduced NOTCH signaling and enhanced the in vitro and in vivo response of HNSCCs to cisplatin and radiation, suggesting combination therapy may increase clinical benefit. A clinical trial has recently completed accrual (NCT02555644).

中文翻译：

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CHK1/2 抑制剂 Prexasertib 在头颈部鳞状细胞癌中抑制 NOTCH 信号并增强顺铂和放射的细胞毒性

以铂类为基础的放化疗是头颈部鳞状细胞癌 (HNSCC) 患者保留器官的主要疗法。然而，这种疾病最终会对治疗产生抗药性，需要新的疗法。检查点激酶 1 和 2 (CHK1/2) 是丝氨酸/苏氨酸激酶，可激活细胞周期检查点并在 DNA 损伤反应 (DDR) 中发挥关键作用。由于对顺铂和辐射的抵抗可能涉及 DDR 升高，我们假设 prexasertib，一种 CHK1/2 抑制剂，可能会增强顺铂和辐射诱导的 HNSCC 细胞毒性。在这项研究中，我们发现 prexasertib 与顺铂和放疗的结合显着降低了有和没有放疗的 HNSCC 细胞系的体外存活率。存活率降低伴随着 DNA 修复检查点激活的抑制，导致持续的 DNA 损伤和细胞凋亡增加。此外，PanCancer Pathways Panel 的 NanoString 分析显示，prexasertib 下调了 NOTCH 信号传导靶基因（NOTCH1、NOTCH2 和 NOTCH3）及其相关配体（JAG1、JAG2、SKP2、MAML2 和 DLL1）。Prexasertib 还降低了 NOTCH1、NOTCH3 和 HES1 蛋白的表达。重要的是，在用 prexasertib、顺铂和放疗处理的人乳头瘤病毒 (HPV) 阳性 UM-SCC47 和 HPV 阴性 UM-SCC1 细胞系异种移植物中观察到显着的肿瘤生长延迟，而没有增加毒性，如小鼠体重测量. 综合起来，prexasertib 降低了 NOTCH 信号并增强了 HNSCCs 对顺铂和放疗的体外和体内反应，表明联合治疗可能会增加临床获益。最近完成了一项临床试验（NCT02555644）。