共济失调毛细血管扩张和 Rad3 相关蛋白 (ATR) 是 DNA 损伤反应的关键组成部分，也是癌症治疗的潜在靶点。评估了 ATR 抑制剂 BAY 1895344 在分化型甲状腺癌 (DTC) 治疗中的应用。 BAY 1895344 以剂量依赖性方式抑制四种 DTC 细胞系（TPC1、K1、FTC-133 和 FTC-238）的细胞活力。 BAY 1895344 处理将 DTC 细胞阻滞在 G2/M 期，增加 caspase-3 活性，并引起细胞凋亡。 BAY 1895344 与索拉非尼或乐伐替尼联合在四种 DTC 细胞系中主要显示出协同作用。 BAY 1895344 与达拉非尼加曲美替尼的组合在携带 BRAFV600E 的 K1 细胞中显示出协同作用。 BAY 1895344 单一疗法可延缓异种移植模型中 K1 和 FTC-133 肿瘤的生长。在 K1 异种移植模型中，BAY 1895344 加乐伐替尼和 BAY 1895344 与达拉非尼加曲美替尼的组合比任何单一疗法更有效。在接受单一疗法或联合疗法治疗的动物中没有出现明显的毒性。我们的研究结果为 BAY 1895344 治疗 DTC 的临床试验的开展提供了理论基础。

Ataxia telangiectasia and Rad3-related protein (ATR) is a critical component of the DNA damage response and a potential target in the treatment of cancers. An ATR inhibitor, BAY 1895344, was evaluated for its use in differentiated thyroid cancer (DTC) therapy. BAY 1895344 inhibited cell viability in four DTC cell lines (TPC1, K1, FTC-133, and FTC-238) in a dose-dependent manner. BAY 1895344 treatment arrested DTC cells in the G2/M phase, increased caspase-3 activity, and caused apoptosis. BAY 1895344 in combination with either sorafenib or lenvatinib showed mainly synergistic effects in four DTC cell lines. The combination of BAY 1895344 with dabrafenib plus trametinib revealed synergistic effects in K1 cells that harbor BRAFV600E. BAY 1895344 monotherapy retarded the growth of K1 and FTC-133 tumors in xenograft models. The combinations of BAY 1895344 plus lenvatinib and BAY 1895344 with dabrafenib plus trametinib were more effective than any single therapy in a K1 xenograft model. No appreciable toxicity appeared in animals treated with either a single therapy or a combination treatment. Our findings provide the rationale for the development of clinical trials of BAY 1895344 in the treatment of DTC.