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Understanding the mechanism of cell death in gemcitabine resistant pancreatic ductal adenocarcinoma: A systems biology approach
Current Genomics ( IF 2.6 ) Pub Date : 2020-01-01 , DOI: 10.2174/1389202920666191025102726
Imlimaong Aier 1 , Pritish K Varadwaj 1
Affiliation  

Background: Gemcitabine is the standard chemotherapeutic drug administered in advanced Pancreatic Ductal Adenocarcinoma (PDAC). However, due to drug resistance in PDAC patients, this treatment has become less effective. Over the years, clinical trials for the quest of finding novel compounds that can be used in combination with gemcitabine have met very little success. Objective: To predict the driving factors behind pancreatic ductal adenocarcinoma, and to understand the effect of these components in the progression of the disease and their contribution to cell growth and proliferation. Methods: With the help of systems biology approaches and using gene expression data, which is generally found in abundance, dysregulated elements in key signalling pathways were predicted. Prominent dysregulated elements were integrated into a model to simulate and study the effect of gemcitabine-induced hypoxia. Results: In this study, several transcription factors in the form of key drivers of cancer-related genes were predicted with the help of CARNIVAL, and the effect of gemcitabine-induced hypoxia on the apoptosis pathway was shown to have an effect on the downstream elements of two primary pathway models; EGF/VEGF and TNF signalling pathway. Conclusion: It was observed that EGF/VEGF signalling pathway played a major role in inducing drug resistance through cell growth, proliferation, and avoiding cell death. Targeting the major upstream components of this pathway could potentially lead to successful treatment.

中文翻译:

了解吉西他滨耐药性胰腺导管腺癌的细胞死亡机制:系统生物学方法

背景:吉西他滨是晚期胰腺导管腺癌 (PDAC) 的标准化疗药物。然而,由于PDAC患者的耐药性,这种治疗方法已经变得不太有效。多年来,寻找可与吉西他滨联合使用的新型化合物的临床试验几乎没有取得成功。目的:预测胰腺导管腺癌背后的驱动因素,并了解这些成分在疾病进展中的作用及其对细胞生长和增殖的贡献。方法:借助系统生物学方法并使用普遍存在的大量基因表达数据,预测关键信号通路中失调的元件。将突出的失调元件整合到模型中,以模拟和研究吉西他滨引起的缺氧的影响。结果:本研究在CARNIVAL的帮助下预测了癌症相关基因关键驱动因子的几种转录因子,并且吉西他滨诱导的缺氧对细胞凋亡途径的影响被证明对下游元件有影响两个主要途径模型;EGF/VEGF 和 TNF 信号通路。结论:观察到EGF/VEGF信号通路在通过细胞生长、增殖和避免细胞死亡诱导耐药性中发挥重要作用。针对该途径的主要上游成分可能会导致成功的治疗。
更新日期:2020-01-01
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