Department of Physics and Astronomy, University of Bologna, Viale Berti Pichat 6/2, 40127, Bologna, Italy.
CAPES Foundation, Ministry of Education of Brazil - Setor Bancário Norte (SBN), Quadra 2, Bloco L, Lote 06, Edifício CAPES, 70.040-031, Brasília, DF, Brazil.
Nat Commun. 2018 Oct 30;9(1):4514. doi: 10.1038/s41467-018-06992-7.
We characterize different tumour types in search for multi-tumour drug targets, in particular aiming for drug repurposing and novel drug combinations. Starting from 11 tumour types from The Cancer Genome Atlas, we obtain three clusters based on transcriptomic correlation profiles. A network-based analysis, integrating gene expression profiles and protein interactions of cancer-related genes, allows us to define three cluster-specific signatures, with genes belonging to NF-κB signaling, chromosomal instability, ubiquitin-proteasome system, DNA metabolism, and apoptosis biological processes. These signatures have been characterized by different approaches based on mutational, pharmacological and clinical evidences, demonstrating the validity of our selection. Moreover, we define new pharmacological strategies validated by in vitro experiments that show inhibition of cell growth in two tumour cell lines, with significant synergistic effect. Our study thus provides a list of genes and pathways that could possibly be used, singularly or in combination, for the design of novel treatment strategies.
我们对不同的肿瘤类型进行了特征描述,以期找到多肿瘤药物靶点,尤其是针对药物再利用和新的药物组合。我们从癌症基因组图谱中的 11 种肿瘤类型开始,根据转录组相关性图谱获得了三个聚类。基于网络的分析,整合了癌症相关基因的基因表达谱和蛋白质相互作用,使我们能够定义三个聚类特异性特征,其中包含 NF-κB 信号通路、染色体不稳定性、泛素-蛋白酶体系统、DNA 代谢和细胞凋亡等生物学过程的基因。这些特征已经通过基于突变、药理学和临床证据的不同方法进行了表征,证明了我们选择的有效性。此外,我们还定义了新的药理学策略,通过体外实验验证了它们在两种肿瘤细胞系中抑制细胞生长的效果,具有显著的协同作用。因此,我们的研究提供了一组可能单独或联合使用的基因和途径,用于设计新的治疗策略。