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Multiomic Profiling of Tyrosine Kinase Inhibitor-Resistant K562 Cells Suggests Metabolic Reprogramming To Promote Cell Survival.
Journal of Proteome Research ( IF 3.8 ) Pub Date : 2019-02-21 , DOI: 10.1021/acs.jproteome.9b00028 Brett M Noel 1, 2 , Steven B Ouellette 2 , Laura Marholz 1 , Deborah Dickey 1 , Connor Navis 1 , Tzu-Yi Yang 1 , Vinh Nguyen 1 , Sarah J Parker 3 , David Bernlohr 1 , Zohar Sachs 4 , Laurie L Parker 1
Journal of Proteome Research ( IF 3.8 ) Pub Date : 2019-02-21 , DOI: 10.1021/acs.jproteome.9b00028 Brett M Noel 1, 2 , Steven B Ouellette 2 , Laura Marholz 1 , Deborah Dickey 1 , Connor Navis 1 , Tzu-Yi Yang 1 , Vinh Nguyen 1 , Sarah J Parker 3 , David Bernlohr 1 , Zohar Sachs 4 , Laurie L Parker 1
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Resistance to chemotherapy can occur through a wide variety of mechanisms. Resistance to tyrosine kinase inhibitors (TKIs) often arises from kinase mutations-however, "off-target" resistance occurs but is poorly understood. Previously, we established cell line resistance models for three TKIs used in chronic myeloid leukemia treatment, and found that resistance was not attributed entirely to failure of kinase inhibition. Here, we performed global, integrated proteomic and transcriptomic profiling of these cell lines to describe mechanisms of resistance at the protein and gene expression level. We used whole transcriptome sequencing and SWATH-based data-independent acquisition mass spectrometry (DIA-MS), which does not require isotopic labels and provides quantitative measurements of proteins in a comprehensive, unbiased fashion. The proteomic and transcriptional data were correlated to generate an integrated understanding of the gene expression and protein alterations associated with TKI resistance. We defined mechanisms of resistance and two novel markers, CA1 and alpha-synuclein, that were common to all TKIs tested. Resistance to all of the TKIs was associated with oxidative stress responses, hypoxia signatures, and apparent metabolic reprogramming of the cells. Metabolite profiling and glucose-dependence experiments showed that resistant cells had routed their metabolism through glycolysis (particularly through the pentose phosphate pathway) and exhibited disruptions in mitochondrial metabolism. These experiments are the first to report a global, integrated proteomic, transcriptomic, and metabolic analysis of TKI resistance. These data suggest that although the mechanisms are complex, targeting metabolic pathways along with TKI treatment may overcome pan-TKI resistance.
中文翻译：
耐酪氨酸激酶抑制剂的K562细胞的多组学分析表明代谢重编程，以促进细胞存活。
对化学疗法的抗性可以通过多种机制发生。对酪氨酸激酶抑制剂（TKIs）的耐药性通常是由激酶突变引起的，但是，发生了“脱靶”耐药性，但了解甚少。以前，我们建立了用于慢性粒细胞白血病治疗的三种TKI的细胞系耐药性模型，发现耐药性并不完全归因于激酶抑制作用的失败。在这里，我们对这些细胞系进行了整体的，综合的蛋白质组学和转录组学分析，以描述在蛋白质和基因表达水平上的抗性机制。我们使用了完整的转录组测序和基于SWATH的独立于数据的采集质谱（DIA-MS），该方法不需要同位素标记，并且可以以全面，公正的方式对蛋白质进行定量测量。蛋白质组学和转录数据相关，以产生对与TKI抗性相关的基因表达和蛋白质改变的综合理解。我们定义了抗药性的机制和两个新标记，CA1和α-突触核蛋白，这是所有测试的TKI所共有的。对所有TKI的抗性与细胞的氧化应激反应，缺氧信号和表观代谢重编程有关。代谢物谱分析和葡萄糖依赖性实验表明，抗性细胞通过糖酵解（尤其是通过戊糖磷酸途径）引导了它们的新陈代谢，并在线粒体新陈代谢中表现出破坏。这些实验是第一个报告TKI抗性的整体，蛋白质组学，转录组学和代谢分析的实验。
更新日期：2019-02-22
中文翻译：
耐酪氨酸激酶抑制剂的K562细胞的多组学分析表明代谢重编程，以促进细胞存活。
对化学疗法的抗性可以通过多种机制发生。对酪氨酸激酶抑制剂（TKIs）的耐药性通常是由激酶突变引起的，但是，发生了“脱靶”耐药性，但了解甚少。以前，我们建立了用于慢性粒细胞白血病治疗的三种TKI的细胞系耐药性模型，发现耐药性并不完全归因于激酶抑制作用的失败。在这里，我们对这些细胞系进行了整体的，综合的蛋白质组学和转录组学分析，以描述在蛋白质和基因表达水平上的抗性机制。我们使用了完整的转录组测序和基于SWATH的独立于数据的采集质谱（DIA-MS），该方法不需要同位素标记，并且可以以全面，公正的方式对蛋白质进行定量测量。蛋白质组学和转录数据相关，以产生对与TKI抗性相关的基因表达和蛋白质改变的综合理解。我们定义了抗药性的机制和两个新标记，CA1和α-突触核蛋白，这是所有测试的TKI所共有的。对所有TKI的抗性与细胞的氧化应激反应，缺氧信号和表观代谢重编程有关。代谢物谱分析和葡萄糖依赖性实验表明，抗性细胞通过糖酵解（尤其是通过戊糖磷酸途径）引导了它们的新陈代谢，并在线粒体新陈代谢中表现出破坏。这些实验是第一个报告TKI抗性的整体，蛋白质组学，转录组学和代谢分析的实验。
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