Graves Occam Kelly, Kim Woonghee, Özcan Mehmet, Ashraf Sajda, Turkez Hasan, Yuan Meng, Zhang Cheng, Mardinoglu Adil, Li Xiangyu
Harvey Mudd College, Claremont, CA 91711, USA.
Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm SE-17165, Sweden.
Biomed Pharmacother. 2023 May;161:114486. doi: 10.1016/j.biopha.2023.114486. Epub 2023 Mar 10.
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.
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.
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.
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.
肺腺癌（LUAD）是肺癌中最常见的亚型之一。尽管临床上已使用多种靶向治疗方法，但患者的5年总生存率仍然较低。因此，迫切需要确定新的治疗靶点并开发新药来治疗LUAD患者。
采用生存分析来确定预后基因。利用基因共表达网络分析来确定驱动肿瘤发展的枢纽基因。采用基于图谱的药物重新定位方法来重新利用可能对靶向枢纽基因有用的药物。分别使用MTT和LDH测定法来测量细胞活力和药物细胞毒性。蛋白质免疫印迹法用于检测蛋白质的表达。
我们从两个独立的LUAD队列中鉴定出341个一致的预后基因，其高表达与患者的不良生存结果相关。其中，八个基因由于在基因共表达网络分析的关键功能模块中具有较高的中心性而被确定为枢纽基因，这些基因与癌症的各种特征（如DNA复制和细胞周期）相关。我们基于药物重新定位方法对八个基因中的三个（CDCA8、MCM6和TTK）进行了药物重新定位分析。最后，我们重新利用了五种药物来抑制每个靶基因的蛋白质表达水平，并通过体外实验验证了药物疗效。
我们发现了针对不同种族和地理特征的LUAD患者的共同可靶向基因。我们还证明了我们的药物重新定位方法在开发用于疾病治疗的新药方面的可行性。
