Mehrmohamadi Mahya, Jeong Seong Ho, Locasale Jason W
Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710 USA.
Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710 USA.
Cancer Metab. 2017 Oct 3;5:8. doi: 10.1186/s40170-017-0170-3. eCollection 2017.
Antimetabolite chemotherapeutic agents that target cellular metabolism are widely used in the clinic and are thought to exert their anti-cancer effects mainly through non-specific cytotoxic effects. However, patients vary dramatically with respect to treatment outcome, and the sources of heterogeneity remain largely unknown.
Here, we introduce a computational method for identifying gene expression signatures of response to chemotherapies and apply it to human tumors and cancer cell lines. Furthermore, we characterize a set of 17 antimetabolite agents in various contexts to investigate determinants of sensitivity to these agents.
We identify distinct favorable and unfavorable metabolic expression signatures for 5-FU and Gemcitabine. Importantly, we find that metabolic pathways targeted by each of these antimetabolites are specifically enriched in its expression signatures. We provide evidence against the common notion about non-specific cytotoxic functions of antimetabolite drugs.
This study demonstrates through unbiased analyses that the activities of metabolic pathways likely contribute to therapeutic response.
靶向细胞代谢的抗代谢化疗药物在临床上广泛应用，人们认为其抗癌作用主要通过非特异性细胞毒性效应实现。然而，患者的治疗结果差异很大，而异质性的来源在很大程度上仍不清楚。
在此，我们介绍一种用于识别化疗反应基因表达特征的计算方法，并将其应用于人类肿瘤和癌细胞系。此外，我们在各种情况下对一组17种抗代谢药物进行表征，以研究对这些药物敏感性的决定因素。
我们确定了5-氟尿嘧啶和吉西他滨不同的有利和不利代谢表达特征。重要的是，我们发现这些抗代谢药物各自靶向的代谢途径在其表达特征中特异性富集。我们提供证据反驳了关于抗代谢药物非特异性细胞毒性功能的普遍观念。
本研究通过无偏分析表明，代谢途径的活性可能有助于治疗反应。
