Zhai Bo, Sun Xue-Ying
Bo Zhai, Xue-Ying Sun, The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital, Harbin Medical University, Harbin 150001, Heilongjiang Province, China.
World J Hepatol. 2013 Jul 27;5(7):345-52. doi: 10.4254/wjh.v5.i7.345.
Sorafenib, the unique drug as first-line treatment for advanced hepatocellular carcinoma (HCC), has opened a window of hope after searching for effective agents to combat HCC for decades. However, the overall outcomes are far from satisfactory. One of the explanations is the genetic heterogeneity of HCC, which has led to identifying predictive biomarkers for primary resistance to sorafenib, and then applying the concept of personalized medicine, or seeking therapeutic strategies such as combining sorafenib with other anticancer agents. Some of the combinations have demonstrated a better effectiveness than sorafenib alone, with good tolerance. The acquired resistance to sorafenib has also drawn attention. As a multikinase inhibitor, sorafenib targets several cellular signaling pathways but simultaneously or sequentially the addiction switches and compensatory pathways are activated. Several mechanisms are involved in the acquired resistance to sorafenib, such as crosstalks involving PI3K/Akt and JAK-STAT pathways, hypoxia-inducible pathways, epithelial-mesenchymal transition, etc. Based on the investigated mechanisms, some other molecular targeted drugs have been applied as second-line treatment for treat HCC after the failure of sorafenib therapy and more are under evaluation in clinical trials. However, the exact mechanisms accounting for sorafenib resistance remains unclear. Further investigation on the crosstalk and relationship of associated pathways will better our understanding of the mechanisms and help to find effective strategies for overcoming sorafenib resistance in HCC.
索拉非尼作为晚期肝细胞癌（HCC）一线治疗的唯一药物，在历经数十年寻找有效抗HCC药物之后，开启了一扇希望之窗。然而，总体疗效远不尽人意。其中一个原因是HCC的基因异质性，这导致了寻找索拉非尼原发性耐药的预测生物标志物，进而应用个性化医疗的概念，或寻求诸如将索拉非尼与其他抗癌药物联合使用的治疗策略。一些联合用药方案已显示出比单独使用索拉非尼更好的疗效，且耐受性良好。索拉非尼的获得性耐药也引起了关注。作为一种多激酶抑制剂，索拉非尼靶向多种细胞信号通路，但同时或相继成瘾开关和代偿途径被激活。索拉非尼获得性耐药涉及多种机制，如涉及PI3K/Akt和JAK-STAT途径的相互作用、缺氧诱导途径、上皮-间质转化等。基于所研究的机制，一些其他分子靶向药物已被用作索拉非尼治疗失败后HCC的二线治疗药物，更多药物正在临床试验中进行评估。然而，索拉非尼耐药的确切机制仍不清楚。对相关途径的相互作用和关系进行进一步研究，将有助于我们更好地理解这些机制，并有助于找到克服HCC中索拉非尼耐药的有效策略。
