Imatinib mesylate is a receptor tyrosine kinase inhibitor drug with broad applications in cancer therapeutics, for example, in chronic myeloid leukemia and gastrointestinal stromal tumors. In this study, new multi-omics findings in yeast on the mechanism of imatinib are reported, using the model organism Saccharomyces cerevisiae. Whole-genome analysis of the transcriptional response of yeast cells following long-term exposure to imatinib, flux-balance analysis (FBA), and modular analysis of protein/protein interaction network consisting of proteins encoded by differentially expressed genes (DEGs) were performed. DEGs indicated that carbon, nitrogen, starch, sucrose, glyoxylate/dicarboxylate metabolism, valine and leucine degradation, and tricarboxylic acid cycle (TCA) were significantly upregulated. By contrast, ribosome biogenesis, pentose/glucuronate interconversion, tryptophan/pyruvate metabolic pathways, and meiosis were significantly downregulated. FBA revealed that a large set of metabolic pathways was altered by imatinib to compensate cancer-associated metabolic changes. Integration of transcriptome and interactome (protein/protein interactions) data helped to identify the core regulatory genes and pathways through elucidation of the active subnetworks. It appears that imatinib may also contribute to antitumoral immune response in the tumor microenvironment and most of the metabolic rearrangements are at posttranscriptional level. Furthermore, additional support for possible contribution of thiamine/pyridoxal phosphate biosynthesis and mitogen-activated protein kinase pathway to drug resistance is noted. This report advances multi-omics understanding of the mechanism of imatinib, and by extension, offers new molecular avenues toward precision medicine and discovery of novel drug targets in cancer therapeutics.

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通过酵母多组学分析揭示抗癌药物伊马替尼的作用机制

甲磺酸伊马替尼是一种受体酪氨酸激酶抑制剂药物，在癌症治疗中有广泛的应用，例如慢性粒细胞白血病和胃肠道间质瘤。在这项研究中，使用模式生物酿酒酵母，报告了酵母中关于伊马替尼作用机制的多组学新发现. 对酵母细胞长期暴露于伊马替尼后的转录反应进行全基因组分析、通量平衡分析 (FBA) 以及由差异表达基因 (DEG) 编码的蛋白质组成的蛋白质/蛋白质相互作用网络的模块化分析。DEGs 表明碳、氮、淀粉、蔗糖、乙醛酸/二羧酸代谢、缬氨酸和亮氨酸降解以及三羧酸循环 (TCA) 显着上调。相比之下，核糖体生物发生、戊糖/葡萄糖醛酸相互转化、色氨酸/丙酮酸代谢途径和减数分裂显着下调。FBA 显示，伊马替尼改变了大量代谢途径，以补偿癌症相关的代谢变化。转录组和相互作用组（蛋白质/蛋白质相互作用）数据的整合有助于通过阐明活性子网络来识别核心调控基因和途径。伊马替尼似乎也可能有助于肿瘤微环境中的抗肿瘤免疫反应，并且大多数代谢重排处于转录后水平。此外，还注意到对硫胺素/磷酸吡哆醛生物合成和丝裂原活化蛋白激酶途径对耐药性的可能贡献的额外支持。该报告推进了对伊马替尼机制的多组学理解，并进一步为精准医学和癌症治疗中新药物靶点的发现提供了新的分子途径。伊马替尼似乎也可能有助于肿瘤微环境中的抗肿瘤免疫反应，并且大多数代谢重排处于转录后水平。此外，还注意到对硫胺素/磷酸吡哆醛生物合成和丝裂原活化蛋白激酶途径对耐药性的可能贡献的额外支持。该报告推进了对伊马替尼机制的多组学理解，并进一步为精准医学和癌症治疗中新药物靶点的发现提供了新的分子途径。伊马替尼似乎也可能有助于肿瘤微环境中的抗肿瘤免疫反应，并且大多数代谢重排处于转录后水平。此外，还注意到对硫胺素/磷酸吡哆醛生物合成和丝裂原活化蛋白激酶途径对耐药性的可能贡献的额外支持。该报告推进了对伊马替尼机制的多组学理解，并进一步为精准医学和癌症治疗中新药物靶点的发现提供了新的分子途径。注意到对硫胺素/磷酸吡哆醛生物合成和丝裂原活化蛋白激酶途径对耐药性的可能贡献的额外支持。该报告推进了对伊马替尼机制的多组学理解，并进一步为精准医学和癌症治疗中新药物靶点的发现提供了新的分子途径。注意到对硫胺素/磷酸吡哆醛生物合成和丝裂原活化蛋白激酶途径对耐药性的可能贡献的额外支持。该报告推进了对伊马替尼机制的多组学理解，并进一步为精准医学和癌症治疗中新药物靶点的发现提供了新的分子途径。