Department of Microbiology, PO Box 800734, University of Virginia Health System, Charlottesville, VA 22908, USA.
Mol Cancer Ther. 2011 Sep;10(9):1581-90. doi: 10.1158/1535-7163.MCT-10-1033. Epub 2011 Jun 28.
Targeted therapies have often given disappointing results when used as single agents in solid tumors, suggesting the importance of devising rational combinations of targeted drugs. We hypothesized that construction of such combinations could be guided by identification of growth and survival pathways whose activity or expression become upregulated in response to single-agent drug treatment. We mapped alterations in signaling pathways assessed by gene array and protein phosphorylation to identify compensatory signal transduction pathways in prostate cancer xenografts treated with a MAP/ERK kinase (MEK) inhibitor PD325901. In addition to numerous components of the extracellular signal-regulated kinase (ERK) signaling pathway, components of the IKK, hedgehog, and phosphoinositide 3-kinase/Akt/mTOR pathways were upregulated following treatment with PD325901. Combinations of PD325901 with inhibitors of any one of these upregulated pathways provided synergistically greater growth inhibition of in vitro cell growth and survival than the individual drugs alone. Thus, the identification of compensatory signal transduction pathways paves the way for rational combinatorial therapies for the effective treatment of prostate cancer.
靶向治疗在实体肿瘤中作为单一药物使用时往往效果不佳，这表明设计合理的靶向药物组合的重要性。我们假设，通过鉴定在单一药物治疗后活性或表达上调的生长和存活途径，可以指导此类组合的构建。我们通过基因阵列和磷酸化蛋白检测来绘制信号通路的改变，以鉴定用 MEK 抑制剂 PD325901 处理的前列腺癌异种移植物中的补偿性信号转导途径。除了细胞外信号调节激酶（ERK）信号通路的许多组成部分外，IKK、 hedgehog 和磷酸肌醇 3-激酶/ Akt/mTOR 通路的组成部分在 PD325901 治疗后也被上调。PD325901 与这些上调途径之一的抑制剂的组合提供了比单独使用单个药物更协同的体外细胞生长和存活抑制作用。因此，鉴定补偿性信号转导途径为前列腺癌的有效治疗铺平了合理的组合治疗之路。
