title: Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma.
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.
authors.affiliation: 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.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhai
authors.forename: Xue-Ying
authors.initials: XY
authors.lastname: Sun
keywords: Cellular signaling pathway; Clinical trials; Drug resistance; Hepatocellular carcinoma; Sorafenib
references.citation: Cell Signal. 2013 Apr;25(4):931-8
references.pmid: 23333463
references.citation: J Cell Mol Med. 2009 Aug;13(8B):2673-2683
references.pmid: 19220580
references.citation: World J Gastroenterol. 2007 Dec 28;13(48):6478-91
references.pmid: 18161917
references.citation: Med Oncol. 2012 Dec;29(4):2793-9
references.pmid: 22427209
references.citation: Cancer. 2007 Sep 1;110(5):1059-67
references.pmid: 17623837
references.citation: Lancet Oncol. 2013 Jan;14(1):55-63
references.pmid: 23182627
references.citation: Int J Oncol. 2012 Nov;41(5):1593-600
references.pmid: 22965141
references.citation: Eur J Med Chem. 2012 Sep;55:220-7
references.pmid: 22871485
references.citation: Clin Cancer Res. 2012 Apr 1;18(7):1824-6
references.pmid: 22355010
references.citation: N Engl J Med. 2008 Jul 24;359(4):378-90
references.pmid: 18650514
references.citation: Future Oncol. 2012 Aug;8(8):999-1014
references.pmid: 22894672
references.citation: J Pharmacol Exp Ther. 2011 Apr;337(1):155-61
references.pmid: 21205925
references.citation: Anticancer Res. 2010 Dec;30(12):4951-8
references.pmid: 21187475
references.citation: BMC Med. 2009 Aug 24;7:42
references.pmid: 19703270
references.citation: Cancer Lett. 2013 Feb 1;329(1):74-83
references.pmid: 23111106
references.citation: J Hepatol. 2011 May;54(5):1073-8
references.pmid: 21145871
references.citation: J Clin Oncol. 2012 Nov 10;30(32):4026-34
references.pmid: 23008289
references.citation: Future Oncol. 2009 Oct;5(8):1169-79
references.pmid: 19852728
references.citation: Semin Liver Dis. 2013 Feb;33 Suppl 1:S11-9
references.pmid: 23457035
references.citation: Pigment Cell Melanoma Res. 2012 Nov;25(6):819-31
references.pmid: 22883054
references.citation: World J Gastroenterol. 2009 Feb 7;15(5):513-20
references.pmid: 19195051
references.citation: Autophagy. 2011 Oct;7(10):1159-72
references.pmid: 21691147
references.citation: J Clin Oncol. 2005 Sep 20;23(27):6657-63
references.pmid: 16170173
references.citation: Clin Cancer Res. 2012 Apr 1;18(7):2090-8
references.pmid: 22238246
references.citation: Cancer Res. 2006 Dec 15;66(24):11851-8
references.pmid: 17178882
references.citation: Clin Cancer Res. 2010 Nov 1;16(21):5189-99
references.pmid: 20884624
references.citation: Expert Opin Drug Metab Toxicol. 2007 Dec;3(6):805-17
references.pmid: 18028026
references.citation: Int J Oncol. 2011 Jan;38(1):121-31
references.pmid: 21109933
references.citation: Ann Surg Oncol. 2010 Feb;17(2):603-12
references.pmid: 19830497
references.citation: Br J Cancer. 2012 Jun 5;106(12):1997-2003
references.pmid: 22596232
references.citation: Cancer Lett. 2009 Jun 18;278(2):145-155
references.pmid: 19303700
references.citation: CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
references.pmid: 21296855
references.citation: Drug Resist Updat. 2010 Aug-Oct;13(4-5):109-18
references.pmid: 20692200
references.citation: Clin Cancer Res. 2012 Apr 15;18(8):2290-300
references.pmid: 22374331
references.citation: Ann Oncol. 2012 Sep;23 Suppl 9:ix7-608
references.pmid: 23012731
references.citation: Cancer Sci. 2012 Mar;103(3):528-34
references.pmid: 22145922
references.citation: Cancer Chemother Pharmacol. 2012 Mar;69(3):773-80
references.pmid: 22033636
references.citation: Invest New Drugs. 2012 Dec;30(6):2384-90
references.pmid: 22402942
references.citation: Mol Cancer Ther. 2011 Jan;10(1):169-77
references.pmid: 21220499
references.citation: Mol Cancer Ther. 2012 Feb;11(2):452-63
references.pmid: 22180308
references.citation: Biol Pharm Bull. 2011;34(3):433-5
references.pmid: 21372398
references.citation: JAMA. 2010 Nov 17;304(19):2154-60
references.pmid: 21081728
references.citation: J Hepatol. 2011 Aug;55(2):359-68
references.pmid: 21168458
references.citation: Hepatology. 2013 May;57(5):1847-57
references.pmid: 23299930
references.citation: J Hepatol. 2012 Jul;57(1):108-15
references.pmid: 22414764
references.citation: Gastroenterology. 2011 May;140(5):1410-26
references.pmid: 21406195
references.citation: Cancer Chemother Pharmacol. 2010 Oct;66(5):837-44
references.pmid: 20041325
references.citation: BMC Syst Biol. 2009 Sep 04;3:88
references.pmid: 19732446
references.citation: J Hepatol. 2010 Jul;53(1):126-31
references.pmid: 20416968
references.citation: J Clin Oncol. 2009 Feb 20;27(6):843-50
references.pmid: 19139433
references.citation: BMC Med. 2009 Aug 24;7:41
references.pmid: 19698189
references.citation: J Clin Oncol. 2006 Sep 10;24(26):4293-300
references.pmid: 16908937
references.citation: J Hepatol. 2011 Nov;55(5):1041-8
references.pmid: 21354226
references.citation: World J Gastroenterol. 2011 Sep 14;17(34):3922-32
references.pmid: 22025881
references.citation: Oncology. 2010;79(1-2):85-92
references.pmid: 21071995
references.citation: Hepatology. 2011 Mar;53(3):1020-2
references.pmid: 21374666
references.citation: J Gastroenterol Hepatol. 2012 Mar;27(3):418-20
references.pmid: 22353346
references.citation: Ann Surg. 2011 Mar;253(3):453-69
references.pmid: 21263310
references.citation: Cancer. 2003 Dec 15;98(12):2664-70
references.pmid: 14669287
references.citation: Clin Cancer Res. 2012 Oct 15;18(20):5662-71
references.pmid: 22929805
references.citation: Cancer. 2007 Apr 1;109(7):1384-90
references.pmid: 17330837