The DNA damage response (DDR) secures the integrity of the genome of eukaryotic cells. DDR deficiencies can promote tumorigenesis but concurrently may increase dependence on alternative repair pathways. The ataxia telangiectasia and Rad3-related (ATR) kinase plays a central role in the DDR by activating essential signaling pathways of DNA damage repair. Here, we studied the effect of the novel selective ATR kinase inhibitor BAY 1895344 on tumor cell growth and viability. Potent antiproliferative activity was demonstrated in a broad spectrum of human tumor cell lines. BAY 1895344 exhibited strong monotherapy efficacy in cancer xenograft models that carry DNA damage repair deficiencies. The combination of BAY 1895344 with DNA damage–inducing chemotherapy or external beam radiotherapy (EBRT) showed synergistic antitumor activity. Combination treatment with BAY 1895344 and DDR inhibitors achieved strong synergistic antiproliferative activity in vitro, and combined inhibition of ATR and PARP signaling using olaparib demonstrated synergistic antitumor activity in vivo. Furthermore, the combination of BAY 1895344 with the novel, nonsteroidal androgen receptor antagonist darolutamide resulted in significantly improved antitumor efficacy compared with respective single-agent treatments in hormone-dependent prostate cancer, and addition of EBRT resulted in even further enhanced antitumor efficacy. Thus, the ATR inhibitor BAY 1895344 may provide new therapeutic options for the treatment of cancers with certain DDR deficiencies in monotherapy and in combination with DNA damage–inducing or DNA repair–compromising cancer therapies by improving their efficacy.

中文翻译：

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新型 ATR 抑制剂 BAY 1895344 作为单一疗法有效，并与临床前癌症模型中的 DNA 损伤诱导或修复受损疗法联合使用

DNA 损伤反应 (DDR) 确保真核细胞基因组的完整性。DDR 缺陷可促进肿瘤发生，但同时可能增加对替代修复途径的依赖。共济失调毛细血管扩张症和 Rad3 相关 (ATR) 激酶通过激活 DNA 损伤修复的基本信号通路在 DDR 中发挥核心作用。在这里，我们研究了新型选择性 ATR 激酶抑制剂 BAY 1895344 对肿瘤细胞生长和活力的影响。在广谱的人类肿瘤细胞系中证明了有效的抗增殖活性。BAY 1895344 在携带 DNA 损伤修复缺陷的癌症异种移植模型中表现出强大的单一疗法功效。BAY 1895344 与 DNA 损伤诱导化疗或外照射放疗 (EBRT) 的组合显示出协同抗肿瘤活性。BAY 1895344 和 DDR 抑制剂的联合治疗在体外实现了强大的协同抗增殖活性，使用 olaparib 对 ATR 和 PARP 信号的联合抑制显示了体内协同抗肿瘤活性。此外，在激素依赖性前列腺癌中，BAY 1895344 与新型非甾体雄激素受体拮抗剂 darolutamide 的组合与各自的单药治疗相比显着提高了抗肿瘤功效，并且加入 EBRT 导致进一步增强了抗肿瘤功效。因此，ATR 抑制剂 BAY 1895344 可以通过提高疗效，为单一疗法中某些 DDR 缺陷的癌症的治疗提供新的治疗选择，并与 DNA 损伤诱导或 DNA 修复受损的癌症疗法相结合。