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有读书笔记有附件Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks

聚焦生物 添加于 2012-12-26 21:32 | 2351 次阅读 | 0 个评论

  •  作 者

    Lee MJ, Ye AS, Gardino AK, Heijink AM, Sorger PK, MacBeath G, Yaffe MB

  •  摘 要

    Crosstalk and complexity within signaling pathways and their perturbation by oncogenes limit component-by-component approaches to understanding human disease. Network analysis of how normal and oncogenic signaling can be rewired by drugs may provide opportunities to target tumors with high specificity and efficacy. Using targeted inhibition of oncogenic signaling pathways, combined with DNA-damaging chemotherapy, we report that time-staggered EGFR inhibition, but not simultaneous coadministration, dramatically sensitizes a subset of triple-negative breast cancer cells to genotoxic drugs. Systems-level analysis-using high-density time-dependent measurements of signaling networks, gene expression profiles, and cell phenotypic responses in combination with mathematical modeling-revealed an approach for altering the intrinsic state of the cell through dynamic rewiring of oncogenic signaling pathways. This process converts these cells to a less tumorigenic state that is more susceptible to DNA damage-induced cell death by reactivation of an extrinsic apoptotic pathway whose function is suppressed in the oncogene-addicted state.

  •  详细资料

    • 关键词: Antineoplastic Agents/*administration & dosage; *Apoptosis; Breast Neoplasms/*drug therapy/metabolism/pathology; Caspase 8; Cell Line, Tumor; DNA Damage; Drug Therapy, Combination/*methods; Female; Humans; Metabolic Networks and Pathways; Models, Biological; Receptor, Epidermal Growth Factor/*antagonists & inhibitors/metabolism; *Signal Transduction
    • 文献种类:期刊
    • 期刊名称: Cell
    • 期刊缩写: Cell
    • 期卷页: 2012年  第149卷 第4期 780-794页
    • 地址: Department of Biology, David H. Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA
    • ISBN: 0092-8674

  •  所属群组

    分享生物综合  

  • 相关链接 DOI URL 

  •  附 件

    PDF附件Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks 

  •  聚焦生物 的文献笔记  订阅

    指出换个顺序使用抗癌药物，能重排细胞凋亡信号网络，从而增强细胞死亡。

    在这篇文章中，研究人员利用致癌信号通路中抑制剂，联合DNA损伤化疗分析，发现比较于同时使用几种EGFR抑制剂，错开时间来使用EGFR抑制剂，能显著提高一组三阴性乳腺癌细 胞对于基因毒性药物的敏感性。所谓三阴性乳腺癌是指雌激素受体、孕酮受体和HER2检测皆为阴性的乳腺癌，这是最难治疗的癌症亚型之一，因为其生物学特 征，这些癌症不会对内分泌疗法或曲妥珠单抗做出反应。并且研究人员还采用了系列系统分析：高密度时间依赖型信号网络检测分析，基因表达谱分析，以及包含数 学模型的细胞表型应答分析，发现了一种改变细胞内状态的新方法，这一方法主要通过动态重排致癌基因信号通路来实现。这一过程能转变这些细胞的肿瘤状态，使 之能更加容易受到DNA损伤诱导细胞死亡。

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