Laboratory for Systems Biology and Bio-inspired Engineering, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.
Hepatology. 2017 Sep;66(3):855-868. doi: 10.1002/hep.29237. Epub 2017 Jul 20.
Sorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients' survival gain is limited and varies over a wide range depending on pathogenetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucial to achieve efficient control of HCCs. In this study, we utilized a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene list functional enrichment analysis and gene set enrichment analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum stress network model, combined with in vitro experiments, showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low-PDI-expression group.
These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness. (Hepatology 2017;66:855-868).
索拉非尼是唯一被批准用于肝细胞癌（HCC）的靶向药物，但它对患者生存获益的影响是有限的，并且根据发病情况有很大的差异。因此，增强索拉非尼的疗效并找到可靠的预测生物标志物对于实现对 HCC 的有效控制至关重要。在这项研究中，我们通过将 HCC 细胞系对索拉非尼的反应的 mRNA 变化的转录组分析与网络分析相结合，采用系统方法来研究索拉非尼的作用和耐药机制。基因列表功能富集分析和基因集富集分析显示，在存在索拉非尼的情况下，蛋白毒性应激和细胞凋亡模块被激活。对内质网应激网络模型的进一步分析，结合体外实验表明，通过用口服活性蛋白二硫键异构酶（PDI）抑制剂（PACMA 31）引入额外的应激可以协同增强索拉非尼在体外和体内的疗效，这在用小鼠异种移植模型得到了证实。我们还发现，与低 PDI 表达组相比，PDI 高表达的 HCC 患者对索拉非尼表现出耐药性和不良的临床结局。
这些结果表明，PDI 是增强索拉非尼疗效的有前途的治疗靶点，也可以作为预测索拉非尼反应性的生物标志物。（《肝脏病学》2017；66：855-868）。
