Wee1 is a kinase that regulates the G2/M progression by the inhibition of CDK1, which is critical for ensuring DNA damage repair before initiation of mitotic entry. Targeting Wee1 may be a potential strategy in the treatment of anaplastic thyroid cancer, a rare but lethal disease. The therapeutic effects of adavosertib, a Wee1 inhibitor for anaplastic thyroid cancer was evaluated in this study. Adavosertib inhibited cell growth in three anaplastic thyroid cancer cell lines in a dose-dependent manner. Cell cycle analysis revealed cells were accumulated in the G2/M phase. Adavosertib induced caspase-3 activity and led to apoptosis. Adavosertib monotherapy showed significant retardation of the growth of two anaplastic thyroid cancer tumor models. The combination of adavosertib with dabrafenib and trametinib revealed strong synergism in vitro and demonstrated robust suppression of tumor growth in vivo in anaplastic thyroid cancer xenograft models with BRAFV600E mutation. The combination of adavosertib with either sorafenib or lenvatinib also demonstrated synergism in vitro and had strong inhibition of tumor growth in vivo in an anaplastic thyroid cancer xenograft model. No appreciable toxicity appeared in mice treated with either a single agent or combination treatment. Our findings suggest adavosertib holds the promise for the treatment of patients with anaplastic thyroid cancer.

中文翻译：

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adavosertib 治疗对甲状腺未分化癌的疗效。

Wee1 是一种激酶，通过抑制 CDK1 来调节 G2/M 进展，这对于确保在有丝分裂开始前修复 DNA 损伤至关重要。靶向 Wee1 可能是治疗甲状腺未分化癌的一种潜在策略，这是一种罕见但致命的疾病。本研究评估了一种 Wee1 甲状腺未分化癌抑制剂 adavosertib 的治疗效果。Adavosertib 以剂量依赖性方式抑制三种间变性甲状腺癌细胞系的细胞生长。细胞周期分析显示细胞在 G2/M 期积累。Adavosertib 诱导 caspase-3 活性并导致细胞凋亡。Adavosertib 单一疗法显示显着延缓两种间变性甲状腺癌肿瘤模型的生长。在具有 BRAFV600E 突变的间变性甲状腺癌异种移植模型中，adavosertib 与 dabrafenib 和曲美替尼的组合在体外显示出强烈的协同作用，并在体内显示出对肿瘤生长的强大抑制作用。在间变性甲状腺癌异种移植模型中，adavosertib 与索拉非尼或乐伐替尼的组合在体外也表现出协同作用，并在体内对肿瘤生长有很强的抑制作用。在用单一药物或联合治疗的小鼠中没有出现明显的毒性。我们的研究结果表明，adavosertib 有望用于治疗甲状腺未分化癌患者。在间变性甲状腺癌异种移植模型中，adavosertib 与索拉非尼或乐伐替尼的组合在体外也表现出协同作用，并在体内对肿瘤生长有很强的抑制作用。在用单一药物或联合治疗的小鼠中没有出现明显的毒性。我们的研究结果表明，adavosertib 有望用于治疗甲状腺未分化癌患者。在间变性甲状腺癌异种移植模型中，adavosertib 与索拉非尼或乐伐替尼的组合在体外也表现出协同作用，并在体内对肿瘤生长有很强的抑制作用。在用单一药物或联合治疗的小鼠中没有出现明显的毒性。我们的研究结果表明，adavosertib 有望用于治疗甲状腺未分化癌患者。