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Modeling chemotherapy-induced stress to identify rational combination therapies in the DNA damage response pathway
Science Signaling ( IF 7.3 ) Pub Date : 2018-07-24 , DOI: 10.1126/scisignal.aat0229
Ozan Alkan 1 , Birgit Schoeberl 1 , Millie Shah 1 , Alexander Koshkaryev 1 , Tim Heinemann 1 , Daryl C. Drummond 1 , Michael B. Yaffe 2 , Andreas Raue 1
Affiliation  

Cells respond to DNA damage by activating complex signaling networks that decide cell fate, promoting not only DNA damage repair and survival but also cell death. We have developed a multiscale computational model that quantitatively links chemotherapy-induced DNA damage response signaling to cell fate. The computational model was trained and calibrated on extensive data from U2OS osteosarcoma cells, including the cell cycle distribution of the initial cell population, signaling data measured by Western blotting, and cell fate data in response to chemotherapy treatment measured by time-lapse microscopy. The resulting mechanistic model predicted the cellular responses to chemotherapy alone and in combination with targeted inhibitors of the DNA damage response pathway, which we confirmed experimentally. Computational models such as the one presented here can be used to understand the molecular basis that defines the complex interplay between cell survival and cell death and to rationally identify chemotherapy-potentiating drug combinations.



中文翻译:

对化学疗法诱发的应激进行建模,以识别DNA损伤反应途径中的合理组合疗法

细胞通过激活决定细胞命运的复杂信号网络来响应DNA损伤,不仅促进DNA损伤的修复和存活,还促进细胞死亡。我们已经开发了一种多尺度计算模型,该模型将化疗诱导的DNA损伤反应信号定量链接到细胞命运。根据来自U2OS骨肉瘤细胞的大量数据对计算模型进行了训练和校准,这些数据包括初始细胞群的细胞周期分布,通过蛋白质印迹法测量的信号传导数据以及通过延时显微镜测量的化学疗法响应的细胞命运数据。由此产生的机理模型预测了细胞单独对化学疗法的反应以及与DNA损伤反应途径的靶向抑制剂的结合,我们通过实验证实了这一点。

更新日期:2018-07-25
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