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：

---

adavosertib治疗抗变性甲状腺癌的疗效。

Wee1是一种通过抑制CDK1来调节G2 / M进程的激酶，这对于确保在进入有丝分裂之前确保DNA损伤修复至关重要。靶向Wee1可能是治疗间变性甲状腺癌（一种罕见但致命的疾病）的潜在策略。在这项研究中评估了Adavosertib（一种Wee1抑制剂）对间变性甲状腺癌的治疗效果。Adavosertib以剂量依赖性方式抑制三种变性甲状腺癌细胞系中的细胞生长。细胞周期分析显示细胞在G2 / M期积累。Adavosertib诱导caspase-3活性并导致凋亡。Adavosertib单一疗法显示了两种间变性甲状腺癌肿瘤模型的生长显着延迟。adavosertib与dabrafenib和曲美替尼的组合在体外显示出强大的协同作用，并在具有BRAFV600E突变的间变性甲状腺癌异种移植模型中证明了体内肿瘤生长的强大抑制作用。adavosertib与sorafenib或lenvatinib的组合在变性间变性甲状腺癌异种移植模型中也显示出体外协同作用，并且对体内肿瘤的生长具有强烈的抑制作用。在单药或联合治疗的小鼠中均未观察到明显的毒性。我们的发现表明adavosertib具有治疗间变性甲状腺癌患者的希望。adavosertib与sorafenib或lenvatinib的组合在变性间变性甲状腺癌异种移植模型中也显示出体外协同作用，并且对体内肿瘤的生长具有强烈的抑制作用。在单药或联合治疗的小鼠中均未观察到明显的毒性。我们的发现表明adavosertib具有治疗间变性甲状腺癌患者的希望。adavosertib与sorafenib或lenvatinib的组合在变性间变性甲状腺癌异种移植模型中也显示出体外协同作用，并且对体内肿瘤的生长具有强烈的抑制作用。在单药或联合治疗的小鼠中均未观察到明显的毒性。我们的发现表明adavosertib具有治疗间变性甲状腺癌患者的希望。