Metabolic Detection of Bruton's Tyrosine Kinase Inhibition in Mantle Cell Lymphoma Cells.
Metabolic Detection of Bruton's Tyrosine Kinase Inhibition in Mantle Cell Lymphoma Cells.
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DOI：
10.1158/1541-7786.mcr-18-0256
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发表时间：
2019-06
期刊：
影响因子：
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通讯作者：
Wasik MA
中科院分区：
文献类型：
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作者：
Lee SC;Shestov AA;Guo L;Zhang Q;Roman JC;Liu X;Wang HY;Pickup S;Nath K;Lu P;Hofbauer S;Mesaros C;Wang YL;Nelson DS;Schuster SJ;Blair IA;Glickson JD;Wasik MA
目前评估激酶抑制剂在癌症中的作用的方法是次优的。分析癌症代谢对抑制剂的反应变化为更好地理解细胞信号传导和代谢之间的相互作用创造了机会，并且从翻译的角度来看，对抑制剂的反应的潜在早期评估以及治疗优化。我们进行了基因组学、代谢组学和通量组学分析，以评估布鲁顿酪氨酸激酶（BTK）抑制剂伊曲替尼（IBR）在套细胞淋巴瘤（MCL）细胞中的作用机制。我们对这些不同技术产生的数据的综合分析表明，IBR深刻地影响了IBR敏感细胞中的关键代谢途径，包括糖酵解、磷酸戊糖途径、TCA循环和β-内酰胺分解，而对IBR反应不良的细胞的影响要小得多。如对各种MCL细胞系的实验所证明的那样，1H MRS可检测的乳酸盐和丙氨酸浓度的变化成为对IBR反应和耐药性的有希望的生物标志物。对13 C MRS和13 C LC-MS实验数据的代谢网络分析提供了各种细胞内通量和能量贡献的定量估计。谷氨酰胺分解贡献了线粒体ATP产生的50%以上。施用谷氨酰胺酶抑制剂CB-839诱导IBR反应不良细胞的生长抑制。
Current methods to evaluate effects of kinase inhibitors in cancer are suboptimal. Analysis of changes in cancer metabolism in response to the inhibitors creates an opportunity for better understanding of the interplay between cell signaling and metabolism and, from the translational perspective, potential early evaluation of response to the inhibitors as well as treatment optimization. We performed genomic, metabolomic and fluxomic analyses to evaluate the mechanism of action of the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (IBR) in mantle cell lymphoma (MCL) cells. Our comprehensive analysis of the data generated by these diverse technologies revealed that IBR profoundly affected key metabolic pathways in IBR-sensitive cells including glycolysis, pentose phosphate pathway, TCA cycle and glutaminolysis while having much less effects on IBR-poorly responsive cells. Changes in 1H MRS-detectable lactate and alanine concentrations emerged as promising biomarkers of response and resistance to IBR as demonstrated from experiments on various MCL cell lines. The metabolic network analysis on the 13C MRS and 13C LC-MS experimental data provided quantitative estimates of various intracellular fluxes and energy contributions. Glutaminolysis contributed over 50% of mitochondrial ATP production. Administration of the glutaminase inhibitor CB-839 induced growth suppression of the IBR-poorly responsive cells.