文章：

靶向共济失调毛细血管扩张突变与Rad3相关蛋白治疗间变性甲状腺癌

Targeting Ataxia Telangiectasia-Mutated and Rad3-Related for Anaplastic Thyroid Cancer

原文发布日期：22 January 2025

DOI: 10.3390/cancers17030359

类型: Article

开放获取: 是

英文摘要：

Background: Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies and has a poor prognosis. Ataxia telangiectasia mutated and Rad3 related (ATR) is a key regulator for the DNA damage response and a potential target to treat cancer. Methods: We assessed the efficacy of BAY 1895344, an ATR inhibitor, in three ATC cell lines. Results: BAY 1895344 caused dose–response cytotoxicity in three ATC cell lines. BAY 1895344 induced S-phase and G2-phase arrest, activated caspase-3 activity and induced apoptosis in ATC cells. BAY 1895344 meaningfully retarded the tumor growth of an ATC xenograft model. BAY 1895344 therapy, combined with dabrafenib and trametinib, had synergism in vitro and revealed robust tumor growth suppression in vivo in two xenograft models of ATC harboring mutantBRAFV600E. Furthermore, the combination of BAY 1895344 with lenvatinib was more effective than either agent alone in a xenograft model of ATC. Conclusions: These results reveal that BAY 1895344 has potential in treating ATC.

摘要翻译： 

背景：间变性甲状腺癌（ATC）是人类最具侵袭性的恶性肿瘤之一，预后不良。共济失调毛细血管扩张突变和Rad3相关蛋白（ATR）是DNA损伤反应的关键调节因子，也是治疗癌症的潜在靶点。方法：我们在三种ATC细胞系中评估了ATR抑制剂BAY 1895344的疗效。结果：BAY 1895344在三种ATC细胞系中引起剂量依赖性细胞毒性。该药物诱导ATC细胞发生S期和G2期阻滞，激活caspase-3活性并诱导细胞凋亡。在ATC异种移植模型中，BAY 1895344显著延缓了肿瘤生长。在携带BRAFV600E突变的两种ATC异种移植模型中，BAY 1895344联合达拉非尼和曲美替尼在体外显示出协同作用，并在体内表现出强烈的肿瘤生长抑制作用。此外，在ATC异种移植模型中，BAY 1895344与乐伐替尼联合使用比任一单药治疗更有效。结论：这些结果表明BAY 1895344具有治疗ATC的潜力。

原文链接：

Targeting Ataxia Telangiectasia-Mutated and Rad3-Related for Anaplastic Thyroid Cancer