Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, South Korea.
Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology (UST), Seoul, South Korea.
Biomed Chromatogr. 2021 Nov;35(11):e5190. doi: 10.1002/bmc.5190. Epub 2021 Jun 23.
Mammalian or mechanistic target of rapamycin (mTOR) drives its fundamental cellular functions through two distinct catalytic subunits, mTORC1 and mTORC2, and is frequently dysregulated in most cancers. To treat cancers, developed mTOR inhibitors have been classified into first and second generations based on their ability to inhibit single (first-generation) and dual (second-generation) mTOR subunits. However, the underlying metabolic differences due to the effects of first- and second-generation mTOR inhibitors have not been clearly evaluated. In this study, rapamycin (sirolimus) and AZD8055 and PP242 were selected as first- and second-generation mTOR inhibitors, respectively, to evaluate the metabolic differences due to these two generations of mTOR inhibitors after a single oral dose using untargeted metabolomics and lipidomics approaches. The metabolic differences at each time point were compared using multivariate analysis. The multivariate and data analyses showed that metabolic disparity was more prominent within 8 h after drug administration and a broad class of metabolites were affected by the administration of both generations of mTOR inhibitors. Among the metabolite classes, changes in the pattern of fatty acids and glycerophospholipids were opposite, specifically at 4 and 8 h between the two generations of mTOR inhibitors. We speculate that the inhibition of the mTORC2 subunit by the second-generation mTOR inhibitor may have resulted in a distinct metabolic pattern between the first- and second-generation inhibitors. Finally, the findings of this study could assist in a more detailed understanding of the key metabolic differences caused by first- and second-generation mTOR inhibitors.
哺乳动物雷帕霉素靶蛋白（mTOR）通过两个不同的催化亚基 mTORC1 和 mTORC2 驱动其基本的细胞功能，并且在大多数癌症中经常失调。为了治疗癌症，已开发的 mTOR 抑制剂根据其抑制单个（第一代）和双重（第二代）mTOR 亚基的能力分为第一代和第二代。然而，由于第一代和第二代 mTOR 抑制剂的作用，尚未清楚评估潜在的代谢差异。在这项研究中，雷帕霉素（西罗莫司）和 AZD8055 和 PP242 分别被选为第一代和第二代 mTOR 抑制剂，以使用非靶向代谢组学和脂质组学方法评估单次口服给药后这两代 mTOR 抑制剂引起的代谢差异。使用多变量分析比较每个时间点的代谢差异。多变量和数据分析表明，药物给药后 8 小时内代谢差异更为明显，并且两代 mTOR 抑制剂都会影响广泛的代谢物类别。在代谢物类别中，脂肪酸和甘油磷脂的变化模式相反，具体表现为两代 mTOR 抑制剂在 4 小时和 8 小时之间。我们推测第二代 mTOR 抑制剂对 mTORC2 亚基的抑制可能导致两代抑制剂之间存在独特的代谢模式。最后，这项研究的结果可以帮助更详细地了解第一代和第二代 mTOR 抑制剂引起的关键代谢差异。
