Discovery of drug targets and therapeutic agents based on drug repositioning to treat lung adenocarcinoma
Discovery of drug targets and therapeutic agents based on drug repositioning to treat lung adenocarcinoma
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DOI：
10.1016/j.biopha.2023.114486
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发表时间：
2023-03-10
影响因子：
7.5
通讯作者：
Li, Xiangyu
中科院分区：
文献类型：
--
作者：
Graves, Occam Kelly;Kim, Woonghee;Li, Xiangyu
背景：肺腺癌是肺癌中最常见的亚型之一。虽然各种靶向治疗已在临床实践中得到应用，但患者的5年总体生存率仍然较低。因此，寻找新的治疗靶点，开发治疗LUAD的新药已成为当务之急。方法：采用生存分析方法寻找影响预后的基因。基因共表达网络分析用于确定驱动肿瘤发生的中枢基因。一种基于图谱的药物重新定位方法被用来重新定位针对HUB基因的潜在有用的药物。用四甲基偶氮唑盐比色法和乳酸脱氢酶比色法分别检测细胞活力和药物的细胞毒性。用Western印迹法检测各蛋白的表达。结果：我们从两个独立的LUAD队列中确定了341个一致的预后基因，它们的高表达与患者较差的生存结果相关。其中，8个基因被鉴定为Hub基因，因为它们在基因共表达网络分析中的关键功能模块中具有较高的中心性，这些基因与癌症的各种特征(如DNA复制和细胞周期)相关。基于我们的药物重定位方法，我们对八个基因中的三个(CDCA8、MCM6和TTK)进行了药物重定位分析。最后，我们重新设计了五种抑制每个靶基因蛋白表达水平的药物，并通过体外实验验证了药物的有效性。解读：我们发现了治疗不同种族和地理特征的LUAD患者的共识靶向基因。我们还证明了我们的药物重新定位方法在开发治疗疾病的新药方面的可行性。
Background: Lung adenocarcinoma (LUAD) is the one of the most common subtypes in lung cancer. Although various targeted therapies have been used in the clinical practice, the 5-year overall survival rate of patients is still low. Thus, it is urgent to identify new therapeutic targets and develop new drugs for the treatment of the LUAD patients. Methods: Survival analysis was used to identify the prognostic genes. Gene co-expression network analysis was used to identify the hub genes driving the tumor development. A profile-based drug repositioning approach was used to repurpose the potentially useful drugs for targeting the hub genes. MTT and LDH assay were used to measure the cell viability and drug cytotoxicity, respectively. Western blot was used to detect the expression of the proteins. Findings: We identified 341 consistent prognostic genes from two independent LUAD cohorts, whose high expression was associated with poor survival outcomes of patients. Among them, eight genes were identified as hub genes due to their high centrality in the key functional modules in the gene-co-expression network analysis and these genes were associated with the various hallmarks of cancer (e.g., DNA replication and cell cycle). We performed drug repositioning analysis for three of the eight genes (CDCA8, MCM6, and TTK) based on our drug repositioning approach. Finally, we repurposed five drugs for inhibiting the protein expression level of each target gene and validated the drug efficacy by performing in vitro experiments. Interpretation: We found the consensus targetable genes for the treatment of LUAD patients with different races and geographic characteristics. We also proved the feasibility of our drug repositioning approach for the development of new drugs for disease treatment.