Review
Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Hepatol. Jul 27, 2013; 5(7): 345-352
Published online Jul 27, 2013. doi: 10.4254/wjh.v5.i7.345
Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma
Bo Zhai, Xue-Ying Sun
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
Author contributions: Zhai B and Sun XY solely contributed to this paper.
Supported by Grants from the National Natural Scientific Foundation of China, No. 30973474 and 81272467
Correspondence to: Xue-Ying Sun, MD, PhD, Professor, The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China. kevsun88@hotmail.com
Telephone: +86-451-53643628 Fax: +86-451-53643628
Received: March 29, 2013
Revised: June 5, 2013
Accepted: June 13, 2013
Published online: July 27, 2013
Processing time: 118 Days and 0.7 Hours
Abstract

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.

Keywords: Hepatocellular carcinoma; Sorafenib; Drug resistance; Cellular signaling pathway; Clinical trials

Core tip: The primary resistance of hepatocellular carcinoma (HCC) to sorafenib is due to genetic heterogeneity. Thus, seeking predictive biomarkers and combining sorafenib with other anticancer agents for HCC have been launched with varying degrees of success. Sorafenib inhibits several kinase targets but it can also simultaneously or sequentially activate the addiction switches and compensatory pathways, inducing acquired resistance. Some other molecular targeted drugs have been used as second-line treatment for advanced HCC after the failure of sorafenib therapy. Further investigation on the crosstalk and relationship of associated pathways will better our understanding of the mechanisms accounting for sorafenib resistance in HCC.