Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines
Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines
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DOI：
10.1038/onc.2009.277
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发表时间：
2009-12-03
期刊：
影响因子：
8
通讯作者：
Kroemer, G.
中科院分区：
文献类型：
--
作者：
Olaussen, K. A.;Commo, F.;Kroemer, G.
帕唑帕尼和拉帕替尼是两种酪氨酸激酶抑制剂，设计用于抑制VEGF酪氨酸激酶受体1、2和3（帕唑帕尼）以及双重抑制HER 1和HER 2受体（拉帕替尼）。帕唑帕尼还被报道介导对一组选定的其他酪氨酸激酶如PDGFR和c-kit的抑制作用。在这里，我们报告帕唑帕尼和拉帕替尼协同作用，诱导A549非小细胞肺癌细胞凋亡。对激酶组的系统性评估显示，帕唑帕尼和拉帕替尼均抑制数十种不同的酪氨酸激酶，并且它们的组合可以抑制一些酪氨酸激酶（如c-Met）的活性，这些酪氨酸激酶不受或仅部分受两种药物单独使用的影响。我们还发现，帕唑帕尼和拉帕替尼诱导A549细胞转录组的选择性变化，其中一些是特异性的两种药物的组合。对一组不相关的人类癌细胞系的分析揭示了52个基因的特征，其上调或下调反映了帕唑帕尼和拉帕替尼的联合作用。事实上，帕唑帕尼和拉帕替尼对几种不同的非小细胞肺癌细胞以及不相关的癌症产生协同细胞毒性作用。总之，这些结果支持了这样的论点，即应评价酪氨酸激酶抑制剂组合的协同抗肿瘤作用。这样的组合可能导致促存活信号转导通路的“崩溃”，从而导致凋亡性细胞死亡。Oncogene（2009）28，4249-4260; doi：10.1038/onc.2009.277; 2009年9月14日在线发表
Pazopanib and lapatinib are two tyrosine kinase inhibitors that have been designed to inhibit the VEGF tyrosine kinase receptors 1, 2 and 3 (pazopanib), and the HER1 and HER2 receptors in a dual manner (lapatinib). Pazopanib has also been reported to mediate inhibitory effect on a selected panel of additional tyrosine kinases such as PDGFR and c-kit. Here, we report that pazopanib and lapatinib act synergistically to induce apoptosis of A549 non-small-cell lung cancer cells. Systematic assessment of the kinome revealed that both pazopanib and lapatinib inhibited dozens of different tyrosine kinases and that their combination could suppress the activity of some tyrosine kinases (such as c-Met) that were not or only partially affected by either of the two agents alone. We also found that pazopanib and lapatinib induced selective changes in the transcriptome of A549 cells, some of which were specific for the combination of both agents. Analysis of a panel of unrelated human carcinoma cell lines revealed a signature of 52 genes whose up- or downregulation reflected the combined action of pazopanib and lapatinib. Indeed, pazopanib and lapatinib exerted synergistic cytotoxic effects on several distinct non-small-cell lung cancer cells as well as on unrelated carcinomas. Altogether, these results support the contention that combinations of tyrosine kinase inhibitors should be evaluated for synergistic antitumor effects. Such combinations may lead to a 'collapse' of pro-survival signal transduction pathways that leads to apoptotic cell death. Oncogene (2009) 28, 4249-4260; doi: 10.1038/onc.2009.277; published online 14 September 2009