Phosphoproteomics data classify hematological cancer cell lines according to tumor type and sensitivity to kinase inhibitors.
Phosphoproteomics data classify hematological cancer cell lines according to tumor type and sensitivity to kinase inhibitors.
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DOI：
10.1186/gb-2013-14-4-r37
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发表时间：
2013-04-29
期刊：
影响因子：
12.3
通讯作者：
Cutillas PR
中科院分区：
文献类型：
--
作者：
Casado P;Alcolea MP;Iorio F;Rodríguez-Prados JC;Vanhaesebroeck B;Saez-Rodriguez J;Joel S;Cutillas PR
基于其对激酶抑制剂的预测反应的肿瘤分类是推进靶向个性化治疗的主要目标。在这里，我们使用磷酸化蛋白质组学方法来研究血液癌细胞系（包括急性髓性白血病、淋巴瘤和多发性骨髓瘤）的生物异质性。使用质谱法在六个生物学重复中定量三种急性髓性白血病、三种淋巴瘤和三种多发性骨髓瘤细胞系中的2，000个磷酸化位点。磷酸化位点的强度根据它们的肿瘤类型将这些癌细胞系分组。此外，7个急性髓性白血病细胞系的磷酸化蛋白质组学分析揭示了一组磷酸化位点，其组合强度与对三种激酶抑制剂的生长抑制反应相关，具有显著的相关系数和倍数变化（在最耐药和最敏感的细胞之间> 100）。基于回归分析的建模表明，磷酸化位点的子集可用于预测对测试药物的反应。磷酸化基序的定量分析表明，耐药和敏感细胞的激酶活性模式不同，但有趣的是，与反应相关的磷酸化不是靶向途径的成员，相反，这些主要是在平行的激酶途径。这项研究表明，磷酸化蛋白质组学数据中编码的激酶激活信息与癌细胞对靶向激酶信号传导的化合物的表型反应非常相关，并且可能有助于鉴定对靶向信号传导网络的药物的耐药性或敏感性的新标志物。
Tumor classification based on their predicted responses to kinase inhibitors is a major goal for advancing targeted personalized therapies. Here, we used a phosphoproteomic approach to investigate biological heterogeneity across hematological cancer cell lines including acute myeloid leukemia, lymphoma, and multiple myeloma. Mass spectrometry was used to quantify 2,000 phosphorylation sites across three acute myeloid leukemia, three lymphoma, and three multiple myeloma cell lines in six biological replicates. The intensities of the phosphorylation sites grouped these cancer cell lines according to their tumor type. In addition, a phosphoproteomic analysis of seven acute myeloid leukemia cell lines revealed a battery of phosphorylation sites whose combined intensities correlated with the growth-inhibitory responses to three kinase inhibitors with remarkable correlation coefficients and fold changes (> 100 between the most resistant and sensitive cells). Modeling based on regression analysis indicated that a subset of phosphorylation sites could be used to predict response to the tested drugs. Quantitative analysis of phosphorylation motifs indicated that resistant and sensitive cells differed in their patterns of kinase activities, but, interestingly, phosphorylations correlating with responses were not on members of the pathway being targeted; instead, these mainly were on parallel kinase pathways. This study reveals that the information on kinase activation encoded in phosphoproteomics data correlates remarkably well with the phenotypic responses of cancer cells to compounds that target kinase signaling and could be useful for the identification of novel markers of resistance or sensitivity to drugs that target the signaling network.
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影响因子：
30.8
作者：
Armstrong, SA;Staunton, JE;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
影响因子：
20.3
作者：
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通讯作者：
Mills GB
影响因子：
56.9
作者：
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通讯作者：
Lander, ES
影响因子：
4.7
作者：
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通讯作者：
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