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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 14, 2015; 21(42): 12059-12070
Published online Nov 14, 2015. doi: 10.3748/wjg.v21.i42.12059
Sorafenib-based combined molecule targeting in treatment of hepatocellular carcinoma
Jian-Jun Gao, Zhen-Yan Shi, Ju-Feng Xia, Yoshinori Inagaki, Wei Tang
Jian-Jun Gao, Zhen-Yan Shi, Department of Pharmacology, School of Pharmaceutical Sciences, Qingdao University, Qingdao 266021, Shandong Province, China
Ju-Feng Xia, Yoshinori Inagaki, Wei Tang, Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
Author contributions: Gao JJ initiated this review, searched the literature and contributed largely to the writing of the manuscript; Shi ZY, Xia JF, Inagaki Y and Tang W contributed with their own opinions to this review, surveyed and advised the literature search, offered suggestions on the structure of this paper, contributed to the writing, reviewed all the versions of the manuscript and gave the final approval of the version to be published.
Conflict-of-interest statement: None of the authors have conflict of interest in respect to this paper.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Jian-Jun Gao, PhD, Department of Pharmacology, School of Pharmaceutical Sciences, Qingdao University, 38 Dengzhou Road, Qingdao 266021, Shandong Province, China. gaojj@qdu.edu.cn
Telephone: +86-532-82991070 Fax: +86-532-82991070
Received: June 3, 2015
Peer-review started: June 6, 2015
First decision: July 13, 2015
Revised: July 28, 2015
Accepted: September 14, 2015
Article in press: September 14, 2015
Published online: November 14, 2015
Processing time: 160 Days and 19.7 Hours
Abstract

Sorafenib is the only and standard systematic chemotherapy drug for treatment of advanced hepatocellular carcinoma (HCC) at the current stage. Although sorafenib showed survival benefits in large randomized phase III studies, its clinical benefits remain modest and most often consist of temporary tumor stabilization, indicating that more effective first-line treatment regimens or second-line salvage therapies are required. The molecular pathogenesis of HCC is very complex, involving hyperactivated signal transduction pathways such as RAS/RAF/MEK/ERK and PI3K/AKT/mTOR and aberrant expression of molecules such as receptor tyrosine kinases and histone deacetylases. Simultaneous or sequential abrogation of these critical pathways or the functions of these key molecules involved in angiogenesis, proliferation, and apoptosis may yield major improvements in the management of HCC. In this review, we summarize the emerging sorafenib-based combined molecule targeting for HCC treatment and analyze the rationales of these combinations.

Keywords: Angiogenesis; Mammalian target of rapamycin; Extracellular-signal regulated kinase; Endothelial growth factor receptor; Histone deacetylases

Core tip: Cancer is regarded as a heterogeneous disease, with no exception of hepatocellular carcinoma (HCC), which requires combined chemotherapy. HCC is not sensitive to most currently used conventional cytotoxic drugs. The approval of sorafenib, a molecular targeted drug that inhibits RAF kinase and several other angiogenesis-related receptor tyrosine kinases, opens a door for systematic treatment of HCC. The pathogenesis of HCC involves hyperactivation of several signal pathways and aberrant expression of some key molecules, suggesting combination treatment may yield major improvements in the management of this disease. The emerging sorafenib-based combination treatments are reviewed in the present article.