Department of Biology, David H. Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA.
Cell. 2012 May 11;149(4):780-94. doi: 10.1016/j.cell.2012.03.031.
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.
信号通路中的串扰和复杂性及其被癌基因的扰乱限制了通过逐个组件的方法来理解人类疾病。对正常和致癌信号如何被药物重新布线的网络分析可能为以高特异性和高效性靶向肿瘤提供机会。我们通过靶向抑制致癌信号通路，结合 DNA 损伤化疗，报告了时间交错的 EGFR 抑制，但不是同时联合给药，显著增强了一组三阴性乳腺癌细胞对遗传毒性药物的敏感性。系统水平分析——使用高密度的信号网络、基因表达谱和细胞表型反应的时变测量，并结合数学建模——揭示了一种通过动态重连致癌信号通路来改变细胞内在状态的方法。这个过程通过重新激活其功能在癌基因成瘾状态下受到抑制的外在凋亡途径，将这些细胞转化为更易发生 DNA 损伤诱导的细胞死亡的、肿瘤形成能力较低的状态。
