Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, 500046, India.
Sci Rep. 2022 May 9;12(1):7540. doi: 10.1038/s41598-022-11214-8.
NRAS, a protein mutated in several cancer types, is involved in key drug resistance mechanisms and is an intractable target. The development of drug resistance is one of the major impediments in targeted therapy. Currently, gene expression data is used as the most predictive molecular profile in pan-cancer drug sensitivity and resistance studies. However, the common regulatory mechanisms that drive drug sensitivity/resistance across cancer types are as yet, not fully understood. We focused on GDSC data on NRAS-mutant pan-cancer cell lines, to pinpoint key signaling targets in direct or indirect associations with NRAS, in order to identify other druggable targets involved in drug resistance. Large-scale gene expression, comparative gene co-expression and protein-protein interaction network analyses were performed on selected drugs inducing drug sensitivity/resistance. We validated our data from cell lines with those obtained from primary tissues from TCGA. From our big data studies validated with independent datasets, protein-coding hub genes FN1, CD44, TIMP1, SNAI2, and SPARC were found significantly enriched in signal transduction, proteolysis, cell adhesion and proteoglycans pathways in cancer as well as the PI3K/Akt-signaling pathway. Further studies of the regulation of these hub/driver genes by lncRNAs revealed several lncRNAs as prominent regulators, with MALAT1 as a possible master regulator. Transcription factor EGR1 may control the transcription rate of MALAT1 transcript. Synergizing these studies, we zeroed in on a pan-cancer regulatory axis comprising EGR1-MALAT1-driver coding genes playing a role. These identified gene regulators are bound to provide new paradigms in pan-cancer targeted therapy, a foundation for precision medicine, through the targeting of these key driver genes in the improvement of multi-drug sensitivity or resistance.
NRAS 是一种在多种癌症类型中发生突变的蛋白质，它参与了关键的耐药机制，是一个难以攻克的靶点。耐药性的发展是靶向治疗的主要障碍之一。目前，基因表达数据被用作泛癌药物敏感性和耐药性研究中最具预测性的分子谱。然而，驱动癌症类型间药物敏感性/耐药性的常见调控机制尚不完全清楚。我们专注于 GDSC 中关于NRAS 突变的泛癌细胞系的数据，以确定与 NRAS 直接或间接相关的关键信号靶点，从而确定其他涉及耐药性的可用药靶。对诱导药物敏感性/耐药性的选定药物进行了大规模基因表达、比较基因共表达和蛋白质-蛋白质相互作用网络分析。我们用 TCGA 中的原发组织数据验证了我们从细胞系中获得的数据。从我们用独立数据集验证的大数据研究中，发现编码蛋白的核心基因 FN1、CD44、TIMP1、SNAI2 和 SPARC 在癌症中显著富集于信号转导、蛋白水解、细胞黏附和蛋白聚糖途径以及 PI3K/Akt 信号通路。进一步研究这些核心/驱动基因的 lncRNA 调控，发现了几个 lncRNA 是重要的调控因子，其中 MALAT1 可能是一个主要的调控因子。转录因子 EGR1 可能控制 MALAT1 转录本的转录率。通过将这些研究协同，我们确定了一个泛癌调控轴，该轴由 EGR1-MALAT1-驱动编码基因组成，发挥作用。这些鉴定出的基因调节剂有望为泛癌靶向治疗提供新的范例，为精准医学奠定基础，通过靶向这些关键驱动基因来提高多药敏感性或耐药性。
