HMS LINCS Center Department of Systems Biology Harvard Medical School Boston, Massachusetts 02115, USA.
Merrimack Pharmaceuticals Cambridge, MA 02139, USA.
Sci Signal. 2013 Sep 24;6(294):ra84. doi: 10.1126/scisignal.2004379.
Identifying factors responsible for variation in drug response is essential for the effective use of targeted therapeutics. We profiled signaling pathway activity in a collection of breast cancer cell lines before and after stimulation with physiologically relevant ligands, which revealed the variability in network activity among cells of known genotype and molecular subtype. Despite the receptor-based classification of breast cancer subtypes, we found that the abundance and activity of signaling proteins in unstimulated cells (basal profile), as well as the activity of proteins in stimulated cells (signaling profile), varied within each subtype. Using a partial least-squares regression approach, we constructed models that significantly predicted sensitivity to 23 targeted therapeutics. For example, one model showed that the response to the growth factor receptor ligand heregulin effectively predicted the sensitivity of cells to drugs targeting the cell survival pathway mediated by PI3K (phosphoinositide 3-kinase) and Akt, whereas the abundance of Akt or the mutational status of the enzymes in the pathway did not. Thus, basal and signaling protein profiles may yield new biomarkers of drug sensitivity and enable the identification of appropriate therapies in cancers characterized by similar functional dysregulation of signaling networks.
确定导致药物反应差异的因素对于靶向治疗的有效使用至关重要。我们在一组乳腺癌细胞系中对信号通路活性进行了分析，这些细胞系在受到生理相关配体刺激前后都进行了分析，结果显示了已知基因型和分子亚型的细胞之间网络活性的可变性。尽管基于受体对乳腺癌亚型进行了分类，但我们发现，在未受刺激的细胞（基础特征）中，信号蛋白的丰度和活性以及受刺激细胞中的蛋白质活性（信号特征）在每个亚型内都存在差异。我们使用偏最小二乘回归方法构建了模型，这些模型可以显著预测对 23 种靶向治疗药物的敏感性。例如，一个模型表明，生长因子受体配体 HRG（人表皮生长因子受体 3）的反应可以有效地预测细胞对 PI3K（磷酸肌醇 3-激酶）和 Akt 介导的细胞存活途径的药物敏感性，而 Akt 的丰度或通路中酶的突变状态则不能。因此，基础和信号蛋白谱可能提供药物敏感性的新生物标志物，并能够在信号网络功能失调相似的癌症中识别合适的治疗方法。
