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.
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


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.

Key Words: 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.

Citation: Zhai B, Sun XY. Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma. World J Hepatol 2013; 5(7): 345-352

Liver cancer is the second most frequent cause of cancer death in men worldwide and hepatocellular carcinoma (HCC) accounts for 70%-85% of the total liver cancer burden[1]. Many lines of clinical investigation indicate that none of the adjuvant therapies is particularly effective in treating HCC after surgery and systemic traditional chemotherapy has a very low response rate for HCC. Recently emerging molecular targeted drugs (MTD) have been demonstrated to be promising agents in prolonging the overall survival (OS) of late stage HCC patients. Particularly, sorafenib has been uniquely recommended as the first line treatment for advanced HCC[2]. Despite the encouraging achievement, the worry about drug resistance to sorafenib is increasing as the OS of HCC patients after sorafenib treatment was only 2-3 mo longer than placebo and sorafenib was shown to result in a limited increase in median time to symptomatic progression and a low partial response rate due to drug resistance[3,4]. Although the exact rate of resistance to sorafenib has not been reported, considering the dilemma that no effective systemic therapy is available so far for patients after failure of sorafenib therapy, studies on the mechanisms of sorafenib resistance are urgently required[5-7]. The present article aims to review the latest progress in this field by focusing on the mechanisms of resistance to sorafenib and the strategies in HCC.


Due to genetic heterogeneity, some HCC cells are initially resistant to sorafenib, which is termed primary resistance[8]. The IC50 values of growth inhibition of different HCC cell lines by sorafenib in vitro showed big variations[9,10]. Thus, it is important to identify predictive biomarkers for primary resistance to sorafenib.

The activation of RAF/mitogen-activated protein kinase (MAPK)/extracellular signaling-regulated kinase (ERK) signal pathway is commonly observed in HCC[11]. Sorafenib executes its anti-tumor activity partially through targeting the Raf-1 and B-Raf, thus inhibiting the RAF/MEK/ERK signaling pathways. It was reported that sorafenib inhibited the phosphorylated ERK (pERK) in HCC PLC/PRF/5 and HepG2 cells[9]. Zhang et al[12] reported that the effects of sorafenib on cell proliferation were significantly correlated with basal pERK levels and the U0126, a selective inhibitor of ERK1/2, could reduce the sensitivity of HCC cells to sorafenib through downregulation of pERK. In a phase II clinical study of sorafenib, the pERK levels in tumor samples from 33 patients showed the correlation with median time to progress (TTP)[13]. However, the relationship was not validated in the phase III trial[14]. It has recently been reported that the c-Jun N-terminal kinase (JNK), another member of MAPK family, can serve as a biomarker to predict the sensitivity to sorafenib[15]. Hagiwara et al[15] examined the JNK activity in 39 tumor specimens from advanced HCC before sorafenib treatment and found that the tumors from the non-responder group had higher expression of phospho-c-Jun and JNK activity. Moreover, the JNK activation correlated with decreased TTP and poor OS. A recent study on patients enrolled in the SHARP trial (the phase III, randomized, controlled Sorafenib HCC Assessment Randomized Protocol) investigated predictive biomarkers to sorafenib and showed that the angiogenesis biomarkers Ang2 and VEGF, among ten assessed plasma biomarkers, were independent predictors of the survival of advanced HCC patients. Although the patients with higher soluble c-KIT or lower hepatocyte growth factor (HGF) in sera at baseline showed enhanced survival benefit, neither of them predicted the response to sorafenib[16].

The current available data indicate that candidate biomarkers for sorafenib sensitivity are still of uncertain value. Well-designed prospective clinical studies are required to judge their exact roles in predicting the primary resistance to sorafenib in HCC. In addition, more preclinical studies are also needed to clarify whether the currently known biomarkers are the downstream events of the latent key biomarkers or if these biomarkers vary in individual patients.


Long-term exposure to antitumor drugs often results in reduced sensitivity of the tumor cells to the drug, leading to acquired resistance. Many mechanisms account for acquired resistance to antitumor drugs, such as addiction switching, compensatory pathway because of pathway loops or crosstalk, epithelial-mesenchymal transition (EMT), cancer stem cells, disabling of pro-apoptotic signals, hypoxic microenvironment, etc[17-19]. Recently, some studies have also indicated the correlation between these mechanisms and resistance to sorafenib in HCC.

PI3K/Akt pathway and sorafenib resistance

The phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK pathways are the most critical pathways involved in the development and progression of HCC and are activated or overexpressed in a high proportion of HCC tissues. The parallel PI3K/Akt pathway remains unscathed when sorafenib targets the MAPK pathway and tyrosine kinases by inhibiting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), Ret and c-kit[3]. Considering the existing crosstalk between the PI3K/Akt and MAPK pathways[20], the latent compensatory mechanism of PI3K/Akt pathways in drug resistance to sorafenib has been attracting attention. Sorafenib has been demonstrated to activate Akt and upregulate the phosphorylation of its downstream targets, such as S6K and 4EBP1 in HCC cells[21,22]. A study by Chen et al[7] has shown that sorafenib-resistant HCC cells, which were established by long-term exposure to sorafenib, had increased expression of phosphorylated Akt and p85, a regulatory subunit of PI3K, compared with the parental cells. Similarly, the HCC cells with ectopic expression of constitutive Akt also showed resistance to sorafenib. In addition, the resistance to sorafenib could be reversed by gene knockdown of Akt and Akt inhibitor MK-2206. These results indicate that activation of PI3K/Akt pathway may contribute to sorafenib resistance and call for further study in clinical trials.

JAK-STAT pathway and sorafenib resistance

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway participates in the regulation of cell proliferation, differentiation, survival, motility and apoptosis in many organs, including liver[23,24]. STAT3 plays a critical role in transcriptional regulation of genes and is also activated by many cytokines and growth factor receptors, such as PDGFR, fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (EGFR) through JAK[25,26]. The negative regulation of STAT3 is mainly executed by suppression of cytokine signaling (SOCS) proteins through JAK and Src-homology protein tyrosine phosphatases (SHPs), such as SHP-1 and SHP-2, and cytokines and growth factor receptors[23]. STAT3 is activated in HCC and knockdown of STAT3 had a therapeutic effect on HCC[27]. It has recently been reported that sorafenib inhibited the activity of STAT3 by downregulating the phosphorylation of STAT3 at the tyrosine and serine site (Y705 and S727) through regulating PI3K/Akt pathway and MAPK pathway, respectively, but had no effect on JAK2 and SHP2 expression[27]. Sorafenib displayed its inhibitory effect on STAT3 in an SHP-1-dependent manner, but not kinase-dependent inactivation of STAT3[28]. Sorafenib also overcomes TRAIL resistance by inhibiting the activation of STAT3 in HCC cells[29]. Several studies have also investigated the role of JAK-STAT pathway in the mechanisms of acquired resistance to sorafenib in HCC. Sorafenib-resistant HCC cells express higher levels of p-STAT3, p-JAK1 and p-JAK2, but lower levels of SHP-1 and p-SHP-1, indicating that the JAK-STAT pathway participates in the acquired resistance to sorafenib in HCC[26]. Interestingly, dovitinib, another multikinase inhibitor targeting VEGFR, FGFR and c-KIT and regulating the JAK-STAT pathway, could reverse the acquired resistance to sorafenib by directly activating SHP-1 and thus downregulating p-STAT3[26]. Inhibition of SHP-1 or gene knockdown of SHP-1 blocked the effect of dovitinib, indicating that the SHP-1-activating agent may provide second-line treatment after the failure of sorafenib therapy[30].

Hypoxic microenvironment and sorafenib resistance

The hypoxic microenvironment is closely related to the resistance to many antitumor drugs[19]. We have previously demonstrated that targeting hypoxia-inducible pathways enhanced the antitumor activity of doxorubicin in HCC[4,31]. Although sorafenib downregulates the synthesis of hypoxia-inducible factor (HIF)-1α in HCC cells in vitro and in vivo[32], the correlation of sorafenib resistance and hypoxic microenvironment is attractive because the anti-angiogenic activity of sorafenib is speculated to lead to tumor starvation and subsequent tumor hypoxia[33]. A recent study[34] has shown that sorafenib-resistant HCC tissues had higher expression of HIF-1α than sorafenib-sensitive and pre-treated HCC tissues. In xenograft models, the increased hypoxia because of sustained sorafenib therapy was associated with sorafenib sensitivity. Moreover, EF24, an analogue of curcumin, could synergistically enhance the antitumor effects of sorafenib and overcome sorafenib resistance through inhibiting HIF-1α by sequestering it in cytoplasm and promoting degradation via upregulating (von Hippel-Lindau) VHL.

EMT and sorafenib resistance

Epithelial-mesenchymal transition or transformation (EMT) is the transitional phenomenon of epithelial cells to a mesenchymal phenotype which participates in embryonic development and wound healing, and has recently emerged as a pivotal event in the development of the invasive and metastatic potentials of cancer progression, including HCC[35,36]. EMT is regulated by the upstream pathway such as PI3K/Akt pathway, MAPK, etc[37]. Emerging evidence suggests that EMT is involved in, and targeting EMT can reverse, the resistance of antitumor drugs[38]. Recently, the role of EMT in the resistance of HCC to sunitinib has been reported[39]. A study showed that sorafenib inhibited the HGF-induced EMT in HCC by downregulating SNAI1 expression via the MAPK signaling pathway[37]. The microarray gene expression analysis showed the existence of EMT accompanied by activation of PI3K/Akt and MAPK pathway in sorafenib-resistant HCC cells[40]. The above studies indicate that EMT may be involved in the resistance to sorafenib in HCC but further studies to clarify the specific mechanisms are required.

In addition to the above described mechanisms, some limited studies have also demonstrated that EGFR[10], glucose-regulated protein 78 (GRP78)[41], multidrug resistance protein (MDRP) 2[42], nuclear factor κB (NF-κB)[43,44] and autophagy[45] may be involved in the acquired resistance to sorafenib in HCC.


Although the exact mechanisms of resistance to sorafenib have not yet been fully elucidated, some approaches have been launched to cope with sorafenib resistance in HCC in clinical trials. The completed and ongoing clinical trials for overcoming sorafenib resistance are summarized in Tables 1 and 2, respectively. These trials can be divided into two categories. One is to combine sorafenib with other anticancer drugs and the other is to use other drugs or drug combinations as second-line treatments in HCC patients after the failure of sorafenib therapy.

Table 1 Completed clinical trials for overcoming sorafenib resistance.
Therapeutic strategiesPhasesCasesEfficacy
Combinational therapy
5-fluorouracil plus sorafenib[46]Phase II39SD: 46.2%; median TTP: 8 mo; OS: 13.7 mo
Tegafur/uracil plus sorafenib[47]Phase II53Median PFS: 3.7 mo; median OS: 7.4 mo
Octreotide plus sorafenib[48]Phase II (So.LAR.)50SD: 66%; median TTP: 7.0 mo; median OS: 12 mo
Doxorubicin plus sorafenib vs doxorubicin plus placebo[50]Phase III47 vs 49Median TTP: 6.4 mo vs 2.8 mo; OS: 13.7 mo vs 6.5 mo; PFS: 6.0 mo vs 2.7 mo
Erlotinib plus sorafenib vs erlotinib plus placebo[53,54]Phase III (SEARCH)362Median TTP: 3.2 mo vs 4.0 mo; OS: 9.5 mo vs 8.5 mo
Second-line treatments
Sunitinib[55]Retrospective analysis11SD: 40%; median TTP: 3.2 mo
Brivanib[56]Phase II46SD: 41.3%; RR: 4.3%; DCR: 45.7%; median OS: 9.79 mo
Tivantinib vs placebo[6]Phase II71 vs 36Progressive disease: 65% vs 72%; TTP: 1.6 mo vs 1.4 mo
Gemcitabine plus oxaliplatin[59]Retrospective analysis18Overall RR: 18.8%; SD: 18.8%; median PFS: 3.2 mo; OS: 4.7 mo
Erlotinib plus bevacizumab[61]Phase II10No response or SD; median TTP: 1.81 mo; OS: 4.37 mo
Table 2 Ongoing clinical trials for overcoming sorafenib resistance.
StudiesTherapeutic strategiesPhasesPrimary outcomes
Combinational therapy
NCT01271504E7050 plus sorafenib vs sorafenibPhase IIAdverse event
NCT01033240CS-1008 plus sorafenib vs sorafenibPhase IITTP
NCT01539018Tegafur-uracil plus sorafenib vs sorafenibPhase IITTP
NCT01272557Doxorubicin plus sorafenib vs sorafenibPhase IITTP
NCT01015833Doxorubicin plus sorafenib vs sorafenibPhase IIIOS
NCT01214343Cisplatin/fluorouracil plus sorafenib vs sorafenibPhase IIIOS
Second-line treatments
NCT01507168GC33 vs placeboPhase IIPFS
NCT01273662AxitinibPhase IISD
NCT00717756LenalidomidePhase IIRR
NCT01545804LenalidomidePhase IISD
NCT01567930TemsirolimusPhase IIDisease progression
NCT01180959Erlotinib plus bevacizumabPhase IIPFS
NCT01140347Ramucirumabplus BSC vs placebo plus BSCPhase IIIPFS
NCT01108705Brivanib plus BSC vs placebo plus BSCPhase IIIOS
NCT00825955Brivanib plus BSC vs placebo plus BSCPhase IIIOS
NCT01035229Everolimus plus BSC vs placebo plus BSCPhase IIIOS
Combinational therapy with sorafenib

At present, there are dozens of ongoing clinical trials which are evaluating the therapeutic efficacy of sorafenib in combination with other anticancer agents to treat advanced HCC, according to the database of clinical trials from the United States National Institutes of Health ( ). Some completed clinical trials have been promising to some extent by combining sorafenib with other agents.

In a phase II trial with 39 advanced HCC patients, sorafenib in combination with 5-fluorouracil infusion showed an encouraging disease control rate with the stable disease (SD) rate of 46.2% for a median duration of 16.2 mo, median TTP of 8 mo and OS of 13.7 mo[46].

Metronomic chemotherapy using tegafur/uracil has been shown to enhance the anti-tumor effect of anti-angiogenic agents in preclinical models. In a phase IIstudy with 53 advanced HCC patients, metronomic chemotherapy with tegafur/uracil was safely combined with sorafenib and preliminarily showed the improvement of sorafenib efficacy, with median progression-free survival (PFS) of 3.7 mo and median OS of 7.4 mo[47].

In a multicenter phase II So.LAR. study with 50 advanced HCC patients, the combinational therapy with sorafenib and long-acting octreotide resulted in SD rate of 66%, median TTP of 7.0 mo and median OS of 12 mo[48]. The results suggest that the combination between sorafenib and long-acting octreotide is active and well tolerated in patients with advanced HCC and could represent another efficacious chance for the management of this population[48].

Doxorubicin is considered one of the most effective cytotoxic agents and is widely used in the treatment of HCC, especially via transcatheter arterial chemoembolization (TACE)[4,49]. In a phase III trial, doxorubicin plus sorafenib compared with doxorubicin alone was evaluated in 96 patients with advanced HCC[50]. The sorafenib plus doxorubicin achieved longer median TTP (6.4 mo vs 2.8 mo), OS (13.7 mo vs 6.5 mo) and PFS (6.0 mo vs 2.7 mo) than doxorubicin placebo monotherapy. The only grade 2/3 adverse event of left ventricular dysfunction was seen in one patient in the sorafenib plus doxorubicin group. However, because doxorubicin was used as the controlled arm in this trial, the encouraging outcome was unable to justify that the efficacy was from sorafenib alone or the synergism with doxorubicin. Now, a randomized phase III trial aiming to evaluate the combinational therapy of doxorubicin plus sorafenib compared with sorafenib alone is recruiting participants (, NCT01840592).

Erlotinib, an oral tyrosine kinase inhibitor of EGFR, has shown a modest antitumor activity against HCC[51,52]. To evaluate the effect of sorafenib in combination with erlotinib, a randomized, placebo-controlled, double-blind, phase III study (SEARCH trial, NCT00901901) is being conducted with sorafenib as the controlled arm. However, the preliminary results reported in the 37th European Society for Medical Oncology (ESMO) Congress[53,54] did not show that the addition of erlotinib to sorafenib met the primary endpoint and the median OS and TTP was not statistically different in the experimental and controlled arms.

Second-line treatments

Many anticancer drugs, most of which are MTDs, such as VEGFR inhibitors (axitinib and ramucirumab), mTOR inhibitors (everolimus and temsirolimus), EGFR inhibitor (erlotinib) in combination with VEGFR inhibitor (bevacizumab) and GC33, a recombinant humanized antibody against glypican-3, are being tested as second-line treatments for advanced HCC in clinical trials ( ).

Sunitinib, a multikinase inhibitor targeting the similar receptors to sorafenib, such as VEGFR, PDGFR and RAF, showed a modest antitumor activity in 11 sorafenib-resistant patients with SD in 40% patients and median TTP of 3.2 mo[55]. Undesirably, sunitinib as second-line treatment did not show the antitumor activity in HCC patients with Child-Pugh class B liver cirrhosis because these patients died within 4 mo due to the clinical deterioration of liver function and tumor progression.

Brivanib, a selective dual inhibitor of FGFR and VEGFR, has shown antitumor activity against HCC[56]. A phase II open-label study assessed brivanib as second-line treatment in HCC patients who had failed prior to antiangiogenic treatment, including sorafenib[56]. In 46 enrolled patients, brivanib was administered orally at a dose of 800 mg once daily and the SD, tumor response rate and disease control rate was 41.3%, 4.3% and 45.7%, respectively. The median OS was 9.79 mo. The results show that brivanib may be safe and efficient in treating advanced HCC after sorafenib therapy. However, a press release in July, 2012 from Bristol-Myers Squibb, the manufacturer of brivanib, revealed that brivanib did not meet the primary endpoint of improving overall survival vs placebo in the phase III trial ( ).

Recently, a multicenter, randomized, placebo-controlled, double-blind, phase II study (, NCT00988741) reported the results of using tivantinib, a selective oral inhibitor of MET, as second-line treatment in sorafenib-resistant HCC[6]. Among the 107 enrolled patients, 104 patients had received sorafenib treatment. Seventy-one patients were randomly assigned to receive tivantinib (38 at 360 mg twice daily and 33 at 240 mg twice daily) and 36 patients to receive placebo. At the time of analysis, 46 (65%) patients in the tivantinib group and 26 (72%) of those in the placebo group had progressive disease. After the median follow-up of 5.5 mo, the tivantinib group had a longer TTP than the placebo group (1.6 mo vs 1.4 mo). The 22 (31%) patients with MET-high tumors treated with tivantinib had a median TTP of 2.7 mo, which was significantly longer than that (1.4 mo) for 15 MET-high patients (42%) on placebo. Interestingly, tivantinib at the dose of 240 mg (twice per day) showed slightly longer OS and moderate adverse events compared to the schedule of 360 mg. These results provide an option for second-line treatment of advanced HCC patients, particularly for those with MET-high tumors, after failure of sorafenib and call for further phase III trials. The report may also imply that Met might serve as a predictive biomarker in this case.

A drug combination of gemcitabine plus oxaliplatin has shown antitumor activity again HCC[57,58]. Thus, it was used as second-line treatment in HCC patients after sorafenib pretreatment. In a clinical trial with 18 patients after the failure of sorafenib therapy, gemcitabine plus oxaliplatin treatment showed an overall response rate of 18.8%, SD of 18.8%, PFS of the median 3.2 mo and OS of 4.7 mo with moderate adverse events[59].

Erlotinib plus bevacizumab has shown an apparently synergistic effect with acceptable adverse events as first-line treatment of HCC[60]. To evaluate the effects of erlotinib in combination with bevacizumab as second-line therapy after the failure of sorafenib, a phase II trial is ongoing (, NCT01180959). However, another similar phase II trial executed during the same period showed disappointing interim results[61]. Among the ten recruited patients after first-line sorafenib treatment, no response or SD were achieved and the median TTP and OS was 1.81 and 4.37 mo, respectively. Adverse events were common, with rash in 70%, diarrhea in 50% and malaise in 40% of patients. Thus, this trial was halted after the interim analysis[61]. The results of the ongoing similar trial are expected.


In summary, the mechanisms accounting for the resistance of HCC to sorafenib are complicated and remain unclear. The primary resistance of HCC to sorafenib is possibly due to the genetic heterogeneity. Seeking predictive biomarkers and therapeutic strategies by combining sorafenib with other anticancer agents 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, such as PI3K/Akt and JAK-STAT pathways, tumor hypoxia, EMT, etc., leading to acquired resistance. Some other MTDs have been applied as second-line treatment for advanced HCC after the failure of sorafenib therapy and more are under evaluation in clinical trials. Further investigation on the crosstalk and relationship of associated pathways will better our understanding of the mechanisms and effective strategies for overcoming sorafenib resistance in HCC are being sought.


P- Reviewers Chetty R, IkedaM, Rosenbaum J, Yan MX S- Editor Wen LL L- Editor Roemmele A E- Editor Li JY

1.  Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69-90.  [PubMed]  [DOI]
2.  Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020-1022.  [PubMed]  [DOI]
3.  Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390.  [PubMed]  [DOI]
4.  He C, Sun XP, Qiao H, Jiang X, Wang D, Jin X, Dong X, Wang J, Jiang H, Sun X. Downregulating hypoxia-inducible factor-2α improves the efficacy of doxorubicin in the treatment of hepatocellular carcinoma. Cancer Sci. 2012;103:528-534.  [PubMed]  [DOI]
5.  Villanueva A, Llovet JM. Second-line therapies in hepatocellular carcinoma: emergence of resistance to sorafenib. Clin Cancer Res. 2012;18:1824-1826.  [PubMed]  [DOI]
6.  Santoro A, Rimassa L, Borbath I, Daniele B, Salvagni S, Van Laethem JL, Van Vlierberghe H, Trojan J, Kolligs FT, Weiss A. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol. 2013;14:55-63.  [PubMed]  [DOI]
7.  Chen KF, Chen HL, Tai WT, Feng WC, Hsu CH, Chen PJ, Cheng AL. Activation of phosphatidylinositol 3-kinase/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells. J Pharmacol Exp Ther. 2011;337:155-161.  [PubMed]  [DOI]
8.  O’Connor R, Clynes M, Dowling P, O’Donovan N, O’Driscoll L. Drug resistance in cancer - searching for mechanisms, markers and therapeutic agents. Expert Opin Drug Metab Toxicol. 2007;3:805-817.  [PubMed]  [DOI]
9.  Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006;66:11851-11858.  [PubMed]  [DOI]
10.  Blivet-Van Eggelpoël MJ, Chettouh H, Fartoux L, Aoudjehane L, Barbu V, Rey C, Priam S, Housset C, Rosmorduc O, Desbois-Mouthon C. Epidermal growth factor receptor and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells. J Hepatol. 2012;57:108-115.  [PubMed]  [DOI]
11.  Zhu AX. Predicting the response to sorafenib in hepatocellular carcinoma: where is the evidence for phosphorylated extracellular signaling-regulated kinase (pERK)? BMC Med. 2009;7:42.  [PubMed]  [DOI]
12.  Zhang Z, Zhou X, Shen H, Wang D, Wang Y. Phosphorylated ERK is a potential predictor of sensitivity to sorafenib when treating hepatocellular carcinoma: evidence from an in vitro study. BMC Med. 2009;7:41.  [PubMed]  [DOI]
13.  Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, De Greve J, Douillard JY, Lathia C, Schwartz B. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006;24:4293-4300.  [PubMed]  [DOI]
14.  Villanueva A, Llovet JM. Targeted therapies for hepatocellular carcinoma. Gastroenterology. 2011;140:1410-1426.  [PubMed]  [DOI]
15.  Hagiwara S, Kudo M, Nagai T, Inoue T, Ueshima K, Nishida N, Watanabe T, Sakurai T. Activation of JNK and high expression level of CD133 predict a poor response to sorafenib in hepatocellular carcinoma. Br J Cancer. 2012;106:1997-2003.  [PubMed]  [DOI]
16.  Llovet JM, Peña CE, Lathia CD, Shan M, Meinhardt G, Bruix J. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2012;18:2290-2300.  [PubMed]  [DOI]
17.  Lackner MR, Wilson TR, Settleman J. Mechanisms of acquired resistance to targeted cancer therapies. Future Oncol. 2012;8:999-1014.  [PubMed]  [DOI]
18.  Bagrodia S, Smeal T, Abraham RT. Mechanisms of intrinsic and acquired resistance to kinase-targeted therapies. Pigment Cell Melanoma Res. 2012;25:819-831.  [PubMed]  [DOI]
19.  Bottsford-Miller JN, Coleman RL, Sood AK. Resistance and escape from antiangiogenesis therapy: clinical implications and future strategies. J Clin Oncol. 2012;30:4026-4034.  [PubMed]  [DOI]
20.  Zielinski R, Przytycki PF, Zheng J, Zhang D, Przytycka TM, Capala J. The crosstalk between EGF, IGF, and Insulin cell signaling pathways--computational and experimental analysis. BMC Syst Biol. 2009;3:88.  [PubMed]  [DOI]
21.  Gedaly R, Angulo P, Hundley J, Daily MF, Chen C, Koch A, Evers BM. PI-103 and sorafenib inhibit hepatocellular carcinoma cell proliferation by blocking Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. Anticancer Res. 2010;30:4951-4958.  [PubMed]  [DOI]
22.  Huynh H, Ngo VC, Koong HN, Poon D, Choo SP, Thng CH, Chow P, Ong HS, Chung A, Soo KC. Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma. J Cell Mol Med. 2009;13:2673-2683.  [PubMed]  [DOI]
23.  Smirnova OV, Ostroukhova TY, Bogorad RL. JAK-STAT pathway in carcinogenesis: is it relevant to cholangiocarcinoma progression? World J Gastroenterol. 2007;13:6478-6491.  [PubMed]  [DOI]
24.  Fabregat I. Dysregulation of apoptosis in hepatocellular carcinoma cells. World J Gastroenterol. 2009;15:513-520.  [PubMed]  [DOI]
25.  Wei Z, Jiang X, Qiao H, Zhai B, Zhang L, Zhang Q, Wu Y, Jiang H, Sun X. STAT3 interacts with Skp2/p27/p21 pathway to regulate the motility and invasion of gastric cancer cells. Cell Signal. 2013;25:931-938.  [PubMed]  [DOI]
26.  Tai WT, Cheng AL, Shiau CW, Liu CY, Ko CH, Lin MW, Chen PJ, Chen KF. Dovitinib induces apoptosis and overcomes sorafenib resistance in hepatocellular carcinoma through SHP-1-mediated inhibition of STAT3. Mol Cancer Ther. 2012;11:452-463.  [PubMed]  [DOI]
27.  Gu FM, Li QL, Gao Q, Jiang JH, Huang XY, Pan JF, Fan J, Zhou J. Sorafenib inhibits growth and metastasis of hepatocellular carcinoma by blocking STAT3. World J Gastroenterol. 2011;17:3922-3932.  [PubMed]  [DOI]
28.  Tai WT, Cheng AL, Shiau CW, Huang HP, Huang JW, Chen PJ, Chen KF. Signal transducer and activator of transcription 3 is a major kinase-independent target of sorafenib in hepatocellular carcinoma. J Hepatol. 2011;55:1041-1048.  [PubMed]  [DOI]
29.  Chen KF, Tai WT, Liu TH, Huang HP, Lin YC, Shiau CW, Li PK, Chen PJ, Cheng AL. Sorafenib overcomes TRAIL resistance of hepatocellular carcinoma cells through the inhibition of STAT3. Clin Cancer Res. 2010;16:5189-5199.  [PubMed]  [DOI]
30.  Chen KF, Tai WT, Hsu CY, Huang JW, Liu CY, Chen PJ, Kim I, Shiau CW. Blockade of STAT3 activation by sorafenib derivatives through enhancing SHP-1 phosphatase activity. Eur J Med Chem. 2012;55:220-227.  [PubMed]  [DOI]
31.  Wang J, Ma Y, Jiang H, Zhu H, Liu L, Sun B, Pan S, Krissansen GW, Sun X. Overexpression of von Hippel-Lindau protein synergizes with doxorubicin to suppress hepatocellular carcinoma in mice. J Hepatol. 2011;55:359-368.  [PubMed]  [DOI]
32.  Liu LP, Ho RL, Chen GG, Lai PB. Sorafenib inhibits hypoxia-inducible factor-1α synthesis: implications for antiangiogenic activity in hepatocellular carcinoma. Clin Cancer Res. 2012;18:5662-5671.  [PubMed]  [DOI]
33.  Murakami M, Zhao S, Zhao Y, Chowdhury NF, Yu W, Nishijima K, Takiguchi M, Tamaki N, Kuge Y. Evaluation of changes in the tumor microenvironment after sorafenib therapy by sequential histology and 18F-fluoromisonidazole hypoxia imaging in renal cell carcinoma. Int J Oncol. 2012;41:1593-1600.  [PubMed]  [DOI]
34.  Liang Y, Zheng T, Song R, Wang J, Yin D, Wang L, Liu H, Tian L, Fang X, Meng X. Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1α inhibition in hepatocellular carcinoma. Hepatology. 2013;57:1847-1857.  [PubMed]  [DOI]
35.  Maheswaran T, Rushbrook SM. Epithelial-mesenchymal transition and the liver: role in hepatocellular carcinoma and liver fibrosis. J Gastroenterol Hepatol. 2012;27:418-420.  [PubMed]  [DOI]
36.  van Zijl F, Zulehner G, Petz M, Schneller D, Kornauth C, Hau M, Machat G, Grubinger M, Huber H, Mikulits W. Epithelial-mesenchymal transition in hepatocellular carcinoma. Future Oncol. 2009;5:1169-1179.  [PubMed]  [DOI]
37.  Nagai T, Arao T, Furuta K, Sakai K, Kudo K, Kaneda H, Tamura D, Aomatsu K, Kimura H, Fujita Y. Sorafenib inhibits the hepatocyte growth factor-mediated epithelial mesenchymal transition in hepatocellular carcinoma. Mol Cancer Ther. 2011;10:169-177.  [PubMed]  [DOI]
38.  Wang Z, Li Y, Ahmad A, Azmi AS, Kong D, Banerjee S, Sarkar FH. Targeting miRNAs involved in cancer stem cell and EMT regulation: An emerging concept in overcoming drug resistance. Drug Resist Updat. 2010;13:109-118.  [PubMed]  [DOI]
39.  Marijon H, Dokmak S, Paradis V, Zappa M, Bieche I, Bouattour M, Raymond E, Faivre S. Epithelial-to-mesenchymal transition and acquired resistance to sunitinib in a patient with hepatocellular carcinoma. J Hepatol. 2011;54:1073-1078.  [PubMed]  [DOI]
40.  van Malenstein H, Dekervel J, Verslype C, Van Cutsem E, Windmolders P, Nevens F, van Pelt J. Long-term exposure to sorafenib of liver cancer cells induces resistance with epithelial-to-mesenchymal transition, increased invasion and risk of rebound growth. Cancer Lett. 2013;329:74-83.  [PubMed]  [DOI]
41.  Chiou JF, Tai CJ, Huang MT, Wei PL, Wang YH, An J, Wu CH, Liu TZ, Chang YJ. Glucose-regulated protein 78 is a novel contributor to acquisition of resistance to sorafenib in hepatocellular carcinoma. Ann Surg Oncol. 2010;17:603-612.  [PubMed]  [DOI]
42.  Shibayama Y, Nakano K, Maeda H, Taguchi M, Ikeda R, Sugawara M, Iseki K, Takeda Y, Yamada K. Multidrug resistance protein 2 implicates anticancer drug-resistance to sorafenib. Biol Pharm Bull. 2011;34:433-435.  [PubMed]  [DOI]
43.  Urbanik T, Köhler BC, Boger RJ, Wörns MA, Heeger S, Otto G, Hövelmeyer N, Galle PR, Schuchmann M, Waisman A. Down-regulation of CYLD as a trigger for NF-κB activation and a mechanism of apoptotic resistance in hepatocellular carcinoma cells. Int J Oncol. 2011;38:121-131.  [PubMed]  [DOI]
44.  Wu JM, Sheng H, Saxena R, Skill NJ, Bhat-Nakshatri P, Yu M, Nakshatri H, Maluccio MA. NF-kappaB inhibition in human hepatocellular carcinoma and its potential as adjunct to sorafenib based therapy. Cancer Lett. 2009;278:145-155.  [PubMed]  [DOI]
45.  Shi YH, Ding ZB, Zhou J, Hui B, Shi GM, Ke AW, Wang XY, Dai Z, Peng YF, Gu CY. Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis. Autophagy. 2011;7:1159-1172.  [PubMed]  [DOI]
46.  Petrini I, Lencioni M, Ricasoli M, Iannopollo M, Orlandini C, Oliveri F, Bartolozzi C, Ricci S. Phase II trial of sorafenib in combination with 5-fluorouracil infusion in advanced hepatocellular carcinoma. Cancer Chemother Pharmacol. 2012;69:773-780.  [PubMed]  [DOI]
47.  Hsu CH, Shen YC, Lin ZZ, Chen PJ, Shao YY, Ding YH, Hsu C, Cheng AL. Phase II study of combining sorafenib with metronomic tegafur/uracil for advanced hepatocellular carcinoma. J Hepatol. 2010;53:126-131.  [PubMed]  [DOI]
48.  Prete SD, Montella L, Caraglia M, Maiorino L, Cennamo G, Montesarchio V, Piai G, Febbraro A, Tarantino L, Capasso E. Sorafenib plus octreotide is an effective and safe treatment in advanced hepatocellular carcinoma: multicenter phase II So.LAR. study. Cancer Chemother Pharmacol. 2010;66:837-844.  [PubMed]  [DOI]
49.  Rahbari NN, Mehrabi A, Mollberg NM, Müller SA, Koch M, Büchler MW, Weitz J. Hepatocellular carcinoma: current management and perspectives for the future. Ann Surg. 2011;253:453-469.  [PubMed]  [DOI]
50.  Abou-Alfa GK, Johnson P, Knox JJ, Capanu M, Davidenko I, Lacava J, Leung T, Gansukh B, Saltz LB. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA. 2010;304:2154-2160.  [PubMed]  [DOI]
51.  Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G, Donehower RC, Fitch T, Picus J, Erlichman C. Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol. 2005;23:6657-6663.  [PubMed]  [DOI]
52.  Thomas MB, Chadha R, Glover K, Wang X, Morris J, Brown T, Rashid A, Dancey J, Abbruzzese JL. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer. 2007;110:1059-1067.  [PubMed]  [DOI]
53.  Finn RS. Emerging targeted strategies in advanced hepatocellular carcinoma. Semin Liver Dis. 2013;33 Suppl 1:S11-S19.  [PubMed]  [DOI]
54.  Abstracts of the 37th ESMO (European Society for Medical Oncology) Congress. September 28-October 2, 2012. Vienna, Austria. Ann Oncol. 2012;23 Suppl 9:ix7-608.  [PubMed]  [DOI]
55.  Wörns MA, Schuchmann M, Düber C, Otto G, Galle PR, Weinmann A. Sunitinib in patients with advanced hepatocellular carcinoma after progression under sorafenib treatment. Oncology. 2010;79:85-92.  [PubMed]  [DOI]
56.  Finn RS, Kang YK, Mulcahy M, Polite BN, Lim HY, Walters I, Baudelet C, Manekas D, Park JW. Phase II, open-label study of brivanib as second-line therapy in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2012;18:2090-2098.  [PubMed]  [DOI]
57.  Louafi S, Boige V, Ducreux M, Bonyhay L, Mansourbakht T, de Baere T, Asnacios A, Hannoun L, Poynard T, Taïeb J. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC): results of a phase II study. Cancer. 2007;109:1384-1390.  [PubMed]  [DOI]
58.  Taïeb J, Bonyhay L, Golli L, Ducreux M, Boleslawski E, Tigaud JM, de Baere T, Mansourbakht T, Delgado MA, Hannoun L. Gemcitabine plus oxaliplatin for patients with advanced hepatocellular carcinoma using two different schedules. Cancer. 2003;98:2664-2670.  [PubMed]  [DOI]
59.  Mir O, Coriat R, Boudou-Rouquette P, Ropert S, Durand JP, Cessot A, Mallet V, Sogni P, Chaussade S, Pol S. Gemcitabine and oxaliplatin as second-line treatment in patients with hepatocellular carcinoma pre-treated with sorafenib. Med Oncol. 2012;29:2793-2799.  [PubMed]  [DOI]
60.  Thomas MB, Morris JS, Chadha R, Iwasaki M, Kaur H, Lin E, Kaseb A, Glover K, Davila M, Abbruzzese J. Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma. J Clin Oncol. 2009;27:843-850.  [PubMed]  [DOI]
61.  Yau T, Wong H, Chan P, Yao TJ, Pang R, Cheung TT, Fan ST, Poon RT. Phase II study of bevacizumab and erlotinib in the treatment of advanced hepatocellular carcinoma patients with sorafenib-refractory disease. Invest New Drugs. 2012;30:2384-2390.  [PubMed]  [DOI]