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PTEN 和 DNA-PK 决定了人乳腺癌对 WEE1 抑制的敏感性和恢复能力。

PTEN and DNA-PK determine sensitivity and recovery in response to WEE1 inhibition in human breast cancer.

机构信息

Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.

Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

出版信息

Elife. 2020 Jul 6;9:e57894. doi: 10.7554/eLife.57894.

DOI:10.7554/eLife.57894
PMID:32628111
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7338058/
Abstract

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.

摘要

WEE1 激酶抑制药 AZD1775 在癌症临床试验中显示出可喜的结果，但缺乏预测 AZD1775 反应的标志物。在这里，我们通过全蛋白质组/转录组谱分析研究了一组人乳腺癌（BC）细胞系对 AZD1775 的反应，并鉴定了两种基底样 BC（BLBC）：“PTEN 低”BLBC 对 AZD1775 高度敏感，并且在 AZD1775 去除后无法恢复，而“PTEN 高”BLBC 则恢复。AZD1775 诱导 DNA-PK 的磷酸化，保护细胞免受与复制相关的 DNA 损伤，并促进细胞恢复。删除 DNA-PK 或 PTEN，或抑制 DNA-PK 通过消除复制停滞使恢复的 BLBC 对 AZD1775 敏感，从而允许在存在 DNA 损伤的情况下进行复制。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。总之，我们确定了 PTEN 和 DNA-PK 是 AZD1775 反应中复制检查点阻滞的重要调节因子，并将 PTEN 定义为高效 WEE1 癌症治疗的有前途的生物标志物。

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