激酶抑制是针对各种类型癌症的不断扩展的治疗方法。通常，考虑到激酶抑制剂的主要细胞抑制性质，至少当用作单一药物时，治疗反应的评估是通过标准的体积成像程序完成的，在治疗开始后数周至数月进行。因此，临床迫切需要开发新的监测方法来更迅速地检测对激酶抑制的反应。无创 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激酶抑制反应的生物标志物。我们采用了套细胞淋巴瘤 (MCL) 细胞系，显示出对布鲁顿酪氨酸抑制的显着不同的敏感性激酶 (BTK) 的生长情况，并深入研究了抑制对细胞代谢各个方面的影响，包括使用代谢组学的代谢物合成、通过 Seahorse XF 技术进行的葡萄糖和氧化代谢，以及指标代谢物乳酸、丙氨酸、总胆碱和牛磺酸的浓度通过 1H MRS。有效的 BTK 抑制可深刻抑制关键细胞代谢途径，最重要的是嘧啶和嘌呤合成、柠檬酸 (TCA) 循环、糖酵解以及丙酮酸和谷氨酰胺/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，在 MCL 异种移植模型中，它在体外和体内均显着而快速地降低了乳酸（主要是糖酵解的产物）和丙氨酸（氨基酸代谢指标）的浓度，以及不太普遍的总胆碱浓度。这种减少与淋巴瘤细胞扩增和肿瘤生长的抑制程度直接相关。我们的结果表明，BTK 抑制对细胞代谢产生广泛而深刻的抑制作用，受影响的指标代谢物如乳酸、丙氨酸可能作为早期、敏感的代谢物。 ，以及可通过基于无创 MRS 的成像方法检测到的淋巴瘤患者的可靠抑制生物标志物。这种基于成像的检测也可能适用于其他激酶抑制剂，以及多种淋巴和非淋巴恶性肿瘤。© 2024。这是美国政府的作品，在美国不受版权保护；外国版权保护可能适用。

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.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.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.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.© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.