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Abstract：
BACKGROUND: Inhibition of kinases is the ever-expanding therapeutic approach to various types of cancer. Typically, assessment of the treatment response is accomplished by standard, volumetric imaging procedures, performed weeks to months after the onset of treatment, given the predominantly cytostatic nature of the kinase inhibitors, at least when used as single agents. Therefore, there is a great clinical need to develop new monitoring approaches to detect the response to kinase inhibition much more promptly. Noninvasive 1H magnetic resonance spectroscopy (MRS) can measure in vitro and in vivo concentration of key metabolites which may potentially serve as biomarkers of response to kinase inhibition.
METHODS: We employed mantle cell lymphoma (MCL) cell lines demonstrating markedly diverse sensitivity of inhibition of Bruton\'s tyrosine kinase (BTK) regarding their growth and studied in-depth effects of the inhibition on various aspects of cell metabolism including metabolite synthesis using metabolomics, glucose and oxidative metabolism by Seahorse XF technology, and concentration of index metabolites lactate, alanine, total choline and taurine by 1H MRS.
RESULTS: Effective BTK inhibition profoundly suppressed key cell metabolic pathways, foremost pyrimidine and purine synthesis, the citrate (TCA) cycle, glycolysis, and pyruvate and glutamine/alanine metabolism. It also inhibited glycolysis and amino acid-related oxidative metabolism. Finally, it profoundly and quickly decreased concentration of lactate (a product of mainly glycolysis) and alanine (an indicator of amino acid metabolism) and, less universally total choline both in vitro and in vivo, in the MCL xenotransplant model. The decrease correlated directly with the degree of inhibition of lymphoma cell expansion and tumor growth.
CONCLUSIONS: Our results indicate that BTK inhibition exerts a broad and profound suppressive effect on cell metabolism and that the affected index metabolites such as lactate, alanine may serve as early, sensitive, and reliable biomarkers of inhibition in lymphoma patients detectable by noninvasive MRS-based imaging method. This kind of imaging-based detection may also be applicable to other kinase inhibitors, as well as diverse lymphoid and non-lymphoid malignancies.
METHODS: We employed mantle cell lymphoma (MCL) cell lines demonstrating markedly diverse sensitivity of inhibition of Bruton\'s tyrosine kinase (BTK) regarding their growth and studied in-depth effects of the inhibition on various aspects of cell metabolism including metabolite synthesis using metabolomics, glucose and oxidative metabolism by Seahorse XF technology, and concentration of index metabolites lactate, alanine, total choline and taurine by 1H MRS.
RESULTS: Effective BTK inhibition profoundly suppressed key cell metabolic pathways, foremost pyrimidine and purine synthesis, the citrate (TCA) cycle, glycolysis, and pyruvate and glutamine/alanine metabolism. It also inhibited glycolysis and amino acid-related oxidative metabolism. Finally, it profoundly and quickly decreased concentration of lactate (a product of mainly glycolysis) and alanine (an indicator of amino acid metabolism) and, less universally total choline both in vitro and in vivo, in the MCL xenotransplant model. The decrease correlated directly with the degree of inhibition of lymphoma cell expansion and tumor growth.
CONCLUSIONS: Our results indicate that BTK inhibition exerts a broad and profound suppressive effect on cell metabolism and that the affected index metabolites such as lactate, alanine may serve as early, sensitive, and reliable biomarkers of inhibition in lymphoma patients detectable by noninvasive MRS-based imaging method. This kind of imaging-based detection may also be applicable to other kinase inhibitors, as well as diverse lymphoid and non-lymphoid malignancies.
摘要：
背景：抑制激酶是各种类型癌症的不断扩展的治疗方法。通常,治疗反应的评估是通过标准完成的，体积成像程序，在治疗开始后几周到几个月进行，鉴于激酶抑制剂的主要细胞抑制性质，至少当用作单一药物时。因此,临床上非常需要开发新的监测方法，以更及时地检测对激酶抑制的反应。非侵入性1H磁共振波谱（MRS）可以测量关键代谢物的体外和体内浓度，这些代谢物可能作为对激酶抑制反应的生物标志物。
方法：我们采用了套细胞淋巴瘤（MCL）细胞系，这些细胞系在抑制布鲁顿酪氨酸激酶（BTK）的生长方面表现出明显不同的敏感性，并使用代谢组学研究了这种抑制作用对细胞代谢各个方面的深入影响，包括代谢物合成，通过海马XF技术进行葡萄糖和氧化代谢，和指数代谢物乳酸的浓度，丙氨酸,总胆碱和牛磺酸的1HMRS。
结果：有效的BTK抑制作用极大地抑制了关键的细胞代谢途径，首先是嘧啶和嘌呤的合成，柠檬酸盐（TCA）循环，糖酵解,和丙酮酸和谷氨酰胺/丙氨酸代谢。它还抑制糖酵解和氨基酸相关的氧化代谢。最后,它深刻而迅速地降低了乳酸（主要是糖酵解的产物）和丙氨酸（氨基酸代谢的指标）的浓度，在体外和体内，总胆碱的普遍性较低，在MCL异种移植模型中。减少与淋巴瘤细胞扩增和肿瘤生长的抑制程度直接相关。
结论：我们的结果表明，BTK抑制对细胞代谢具有广泛而深远的抑制作用，并且受影响的指标代谢产物如乳酸，丙氨酸可以作为早期，敏感,通过基于MRS的无创成像方法检测淋巴瘤患者的抑制和可靠的生物标志物。这种基于成像的检测也可能适用于其他激酶抑制剂，以及各种淋巴和非淋巴恶性肿瘤。
方法：我们采用了套细胞淋巴瘤（MCL）细胞系，这些细胞系在抑制布鲁顿酪氨酸激酶（BTK）的生长方面表现出明显不同的敏感性，并使用代谢组学研究了这种抑制作用对细胞代谢各个方面的深入影响，包括代谢物合成，通过海马XF技术进行葡萄糖和氧化代谢，和指数代谢物乳酸的浓度，丙氨酸,总胆碱和牛磺酸的1HMRS。
结果：有效的BTK抑制作用极大地抑制了关键的细胞代谢途径，首先是嘧啶和嘌呤的合成，柠檬酸盐（TCA）循环，糖酵解,和丙酮酸和谷氨酰胺/丙氨酸代谢。它还抑制糖酵解和氨基酸相关的氧化代谢。最后,它深刻而迅速地降低了乳酸（主要是糖酵解的产物）和丙氨酸（氨基酸代谢的指标）的浓度，在体外和体内，总胆碱的普遍性较低，在MCL异种移植模型中。减少与淋巴瘤细胞扩增和肿瘤生长的抑制程度直接相关。
结论：我们的结果表明，BTK抑制对细胞代谢具有广泛而深远的抑制作用，并且受影响的指标代谢产物如乳酸，丙氨酸可以作为早期，敏感,通过基于MRS的无创成像方法检测淋巴瘤患者的抑制和可靠的生物标志物。这种基于成像的检测也可能适用于其他激酶抑制剂，以及各种淋巴和非淋巴恶性肿瘤。
