Makarova A S, Lazarevich N L
Klin Lab Diagn. 2013 Oct(10):66-8, 34-7.
Hepatocellular carcinoma (HCC) is one of the most common neoplasms worldwide. Hepatocarcinogenesis is associated with deregulation of the cell signaling thus targeted therapy can decelerate HCC progression by specific inhibition of alternated signaling cascades. Sorafenib is the only multitarget drug approved for HCC treatment that blocks several crucial oncogenic signaling pathways thus suppressing tumor growth, metastasis and providing survival benefit for subset of patients sensitive to sorafenib. Compensatory activation of other tumorigenic mechanisms may lead to decrease of HCC sensitivity to sorafenib. HCC are heterogenic tumors of epithelial origin, and presence of low-differentiated subpopulations of cancer stem cells or dedifferentiated fibroblastoid cells, that are less sensitive to sorafenib due to resistance to growth-inhibitory action of the drug, promotes HCC resistance to sorafenib. Analysis of the expression profile of genes encoding tissue-specific proteins, components of cell junctions, stem cell and mesenchymal markers can reveal sorafenib-resistant populations in HCC and identify signaling pathways that reduce response to sorafenib. Identification of individual sorafenib resistance mechanisms may be useful for rational choice of an appropriate combination of targeted drugs for retardation of HCC progression and improving the efficacy of therapy
肝细胞癌（HCC）是全球最常见的肿瘤之一。肝癌发生与细胞信号传导失调有关，因此靶向治疗可通过特异性抑制交替的信号级联反应来减缓HCC进展。索拉非尼是唯一被批准用于HCC治疗的多靶点药物，它可阻断多种关键的致癌信号通路，从而抑制肿瘤生长、转移，并为对索拉非尼敏感的部分患者带来生存益处。其他致瘤机制的代偿性激活可能导致HCC对索拉非尼的敏感性降低。HCC是上皮起源的异质性肿瘤，癌干细胞或去分化成纤维样细胞的低分化亚群的存在会促进HCC对索拉非尼的耐药性，因为这些亚群对该药物的生长抑制作用具有抗性，所以对索拉非尼不太敏感。分析编码组织特异性蛋白、细胞连接成分、干细胞和间充质标志物的基因表达谱，可以揭示HCC中的索拉非尼耐药群体，并确定降低对索拉非尼反应的信号通路。识别个体的索拉非尼耐药机制可能有助于合理选择合适的靶向药物组合，以延缓HCC进展并提高治疗效果。
