Synthetic lethality of Chk1 inhibition combined with p53 and/or p21 loss during a DNA damage response in normal and tumor cells.
Synthetic lethality of Chk1 inhibition combined with p53 and/or p21 loss during a DNA damage response in normal and tumor cells.
复制标题
在正常和肿瘤细胞中DNA损伤反应期间，CHK1抑制的合成致死性与p53和/或p21损失相结合。
作者：
细胞周期检查点确保基因组的完整性，并经常在人类癌症中受到损害。正在探索的一种治疗策略利用p53缺陷肿瘤中的检查点缺陷，通过消除Chk1介导的检查点反应，使其对DNA损伤剂敏感。使用小鼠模型，我们证明了p21是细胞如何对正常细胞和肿瘤中DNA损伤和Chk1抑制（联合治疗）的组合做出反应的关键决定因素。p21的丢失比p53的丢失更能使正常细胞对联合治疗敏感，并且增强的致死性被CDK抑制部分阻断。此外，21（p53非依赖性）的基础库提供了p53无效细胞，保护其免受联合治疗的影响。我们的研究结果揭示了p21在保护细胞免受Chk1抑制后的DNA损伤致死效应中的一种新的p53非依赖性功能。由于p21水平在结肠直肠肿瘤的显著部分中是低的，因此预测它们对组合疗法特别敏感。本研究报告的结果支持这一预测。
Cell cycle checkpoints ensure genome integrity and are frequently compromised in human cancers. A therapeutic strategy being explored takes advantage of checkpoint defects in p53 deficient tumors in order to sensitize them to DNA damaging agents by eliminating Chk1-mediated checkpoint responses. Using mouse models, we demonstrated that p21 is a key determinant of how cells respond to the combination of DNA damage and Chk1 inhibition (combination therapy) in normal cells as well as in tumors. Loss of p21 sensitized normal cells to the combination therapy much more than did p53 loss and the enhanced lethality was partially blocked by CDK inhibition. In addition, basal pools of 21 (p53-independent) provided p53 null cells with protection from the combination therapy. Our results uncover a novel p53-independent function for p21 in protecting cells from the lethal effects of DNA damage followed by Chk1inhibition. Since p21 levels are low in a significant fraction of colorectal tumors, they are predicted to be particularly sensitive to the combination therapy. Results reported in this study support this prediction.