Inhibition of WEE1 kinase by AZD1775 has shown promising results in clinical cancer trials, but markers predicting AZD1775 response are lacking. Here we analysed AZD1775 response in a panel of human breast cancer (BC) cell lines by global proteome/transcriptome profiling and identified two groups of basal-like BC (BLBCs): ‘PTEN low’ BLBCs were highly sensitive to AZD1775 and failed to recover following removal of AZD1775, while ‘PTEN high’ BLBCs recovered. AZD1775 induced phosphorylation of DNA-PK, protecting cells from replication-associated DNA damage and promoting cellular recovery. Deletion of DNA-PK or PTEN, or inhibition of DNA-PK sensitized recovering BLBCs to AZD1775 by abrogating replication arrest, allowing replication despite DNA damage. This was linked to reduced CHK1 activation, increased cyclin E levels and apoptosis. In conclusion, we identified PTEN and DNA-PK as essential regulators of replication checkpoint arrest in response to AZD1775 and defined PTEN as a promising biomarker for efficient WEE1 cancer therapy.

中文翻译：

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PTEN 和 DNA-PK 确定响应 WEE1 抑制在人乳腺癌中的敏感性和恢复

AZD1775 对 WEE1 激酶的抑制在临床癌症试验中显示出有希望的结果，但缺乏预测 AZD1775 反应的标记物。在这里，我们通过全局蛋白质组/转录组分析分析了一组人类乳腺癌 (BC) 细胞系中的 AZD1775 反应，并确定了两组基底样 BC (BLBC)：“PTEN 低”BLBC 对 AZD1775 高度敏感且未能恢复去除 AZD1775 后，“PTEN 高”BLBC 恢复。AZD1775 诱导 DNA-PK 磷酸化，保护细胞免受复制相关的 DNA 损伤并促进细胞恢复。DNA-PK 或 PTEN 的缺失，或 DNA-PK 的抑制，通过取消复制停滞使 BLBC 恢复对 AZD1775 敏感，尽管 DNA 受损，但仍允许复制。这与 CHK1 激活减少、细胞周期蛋白 E 水平增加和细胞凋亡有关。综上所述，