A genomic approach to predict synergistic combinations for breast cancer treatment.
A genomic approach to predict synergistic combinations for breast cancer treatment.
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DOI：
10.1038/tpj.2011.48
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发表时间：
2013-02
期刊：
影响因子：
--
通讯作者：
Bild AH
中科院分区：
文献类型：
--
作者：
Soldi R;Cohen AL;Cheng L;Sun Y;Moos PJ;Bild AH
我们利用基因组和生化数据来确定乳腺癌的协同药物方案。为了研究组蛋白脱乙酰酶(HDAC)抑制剂丙戊酸(VPA)和异羟肟酸(SAHA)在乳腺癌中的作用机制，我们利用一系列对这两种药物敏感的乳腺癌细胞株建立并验证了药物反应的基因组图谱。这些基因组图谱随后被用来模拟人类乳腺肿瘤的药物反应，并在多个乳腺肿瘤数据集中显示出VPA和SAHA反应图谱之间的显著相关性，突出了它们相似的作用机制。VPA和SAHA失控的基因集中在细胞周期途径上(贝叶斯因子分别为5.21和5.94，p值分别为10−8.6和10−9)。特别是，VPA和SAHA上调了关键的细胞周期蛋白依赖性激酶(CDK)抑制剂的表达。在两个独立的数据集中，CDK抑制剂处理的癌细胞的基因表达谱变化与细胞对HDAC抑制剂的反应相似。综上所述，这些结果使我们假设VPA和SAHA可能与PD-033299等CDK抑制剂协同作用。实验表明，HDAC和CDK抑制剂在乳腺癌细胞系和患者胸腔积液细胞的原代三维培养中都具有统计上显著的协同作用。因此，HDAC和CDK抑制剂之间的协同关系可能为乳腺癌提供一种有效的联合治疗方案。重要的是，这些研究提供了一个例子，说明如何利用药物反应谱的基因组分析来设计癌症治疗的合理药物组合。
We leverage genomic and biochemical data to identify synergistic drug regimens for breast cancer. In order to study the mechanism of the histone deacetylase (HDAC) inhibitors valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) in breast cancer, we generated and validated genomic profiles of drug response using a series of breast cancer cell lines sensitive to each drug. These genomic profiles were then used to model drug response in human breast tumors and show significant correlation between VPA and SAHA response profiles in multiple breast tumor datasets, highlighting their similar mechanism of action. The genes deregulated by VPA and SAHA converge on the cell cycle pathway (Bayes Factor 5.21, and 5.94, respectively, p-value 10−8.6 and 10−9, respectively). In particular, VPA and SAHA upregulate key cyclin-dependent kinase (CDK) inhibitors. In two independent datasets, cancer cells treated with CDK inhibitors have similar gene expression profile changes to the cellular response to HDAC inhibitors. Together, these results led us to hypothesize that VPA and SAHA may interact synergistically with CDK inhibitors such as PD-033299. Experiments show that HDAC and CDK inhibitors have statistically significant synergy in both breast cancer cell lines and primary 3-dimensional cultures of cells from pleural effusions of patients. Therefore, synergistic relationships between HDAC and CDK inhibitors may provide an effective combinatorial regimen for breast cancer. Importantly, these studies provide an example of how genomic analysis of drug response profiles can be used to design rational drug combinations for cancer treatment.
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