Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks.
Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks.
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DOI：
10.1016/j.cell.2012.03.031
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发表时间：
2012-05-11
期刊：
影响因子：
64.5
通讯作者：
Yaffe MB
中科院分区：
文献类型：
--
作者：
Lee MJ;Ye AS;Gardino AK;Heijink AM;Sorger PK;MacBeath G;Yaffe MB
信号通路内的串扰和复杂性，以及癌基因对它们的干扰，限制了理解人类疾病的逐个成分的方法。对药物如何重新连接正常和致癌信号传导的网络分析可能为以高特异性和有效性靶向肿瘤提供机会。通过使用靶向抑制致癌信号通路并结合 DNA 损伤性化疗，我们报告称，时间错开的 EGFR 抑制（而非同时联合给药）可显着提高三阴性乳腺癌细胞对基因毒性药物的敏感性。系统级分析——使用信号网络、基因表达谱和细胞表型反应的高密度时间依赖性测量与数学模型相结合——揭示了一种通过致癌信号通路的动态重新连接来改变细胞内在状态的方法。这一过程将这些细胞转化为致瘤性较低的状态，这种状态更容易受到 DNA 损伤诱导的细胞死亡的影响，这是通过重新激活外在的凋亡途径来实现的，该途径的功能在癌基因成瘾状态下受到抑制。
Crosstalk and complexity within signaling pathways, and their perturbation by oncogenes, limits component-by-component approaches to understanding human disease. Network analysis of how normal and oncogenic signaling can be re-wired 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 co-administration, 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 re-wiring 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 re-activation of an extrinsic apoptotic pathway whose function is suppressed in the oncogene-addicted state.
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