Phosphorylated ERK is a potential predictor of sensitivity to sorafenib when treating hepatocellular carcinoma: evidence from an in vitrostudy

Zhang, Zhe; Zhou, Xin; Shen, Hujia; Wang, Dexing; Wang, Yanhong

doi:10.1186/1741-7015-7-41

Cited by 130 publications

(115 citation statements)

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“…Therefore, it is important to identify the best prognostic factors that can predict response to sorafenib. Certain studies showed that serum VEGF concentration and extracellular signal-regulated kinase levels were good predictors (26,27); however, other surrogate biomarkers must be explored to evaluate prognosis or the efficacy of treatment with sorafenib HCC. In the present study, the patients were restricted to those with BCLC stage C or BCLC stage B but who had previously experienced TACE failure, for whom sorafenib is the major treatment method (28).…”

Section: Discussionmentioning

confidence: 99%

Peripheral blood neutrophil count as a prognostic factor for patients with hepatocellular carcinoma treated with sorafenib

Yuan

Liang

et al. 2017

Molecular and Clinical Oncology

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Abstract. Sorafenib is currently the only efficient molecular targeted therapy for hepatocellular carcinoma (HCC), although its effect is relatively moderate and variable between individuals. The present study aimed to evaluate the significance of peripheral blood neutrophils in the prognosis of HCC patients treated with sorafenib. A total of 464 patients with HCC were treated with sorafenib at Zhongshan Hospital (Shanghai, China) between January 1st, 2008 and December 31st, 2012, among which 120 patients were enrolled in the study. The optimal cutoff point for low vs. high neutrophil count (3.65x10 9 ) was obtained from a receiver operating characteristic curve. Overall survival (OS) was compared between the patients with low and high peripheral neutrophil counts. Univariate and multivariate analyses were used to explore the prognostic factors associated with OS in the patients treated with sorafenib. A nomogram model was also performed to predict the OS times of these patients. The median OS time was 9.0 months (95% confidence interval, 5.9-12.1 months) in the whole group of patients, with 1-, 2-and 3-year OS rates of 36, 24 and 16%, respectively. Using a cutoff level of 3.65x10 9 neutrophils/l, the median OS time was longer in the group of patients with a low peripheral neutrophil count than in those with a high peripheral neutrophil count (11.5 vs. 5.0 months, respectively; P<0.001). The multivariate analysis showed that peripheral neutrophil count, α-fetoprotein level and tumor size were independent prognostic factors for OS. In addition, using the nomogram model for the prediction of OS, the Harrell's c-index was 0.79. Therefore, it was concluded that a lower peripheral blood neutrophil count was associated with a better prognosis following treatment with sorafenib therapy.

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Section: Discussionmentioning

confidence: 99%

Peripheral blood neutrophil count as a prognostic factor for patients with hepatocellular carcinoma treated with sorafenib

Yuan

Liang

et al. 2017

Molecular and Clinical Oncology

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“…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] .…”

Section: Sensitivitymentioning

confidence: 99%

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

Zhai

Sun²

2013

WJH

163

152

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

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“…Biologic activities of sorafenib and regorafenib can be demonstrated in vitro within a few hours of exposure to 0.1-10 µM of the drugs [8][9][10][11][12][13]. The cytotoxicity is cell specific and includes alterations in multiple signaling pathways, execution of apoptosis, induction of ER stress, and inhibition of protein synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…The cytotoxicity is cell specific and includes alterations in multiple signaling pathways, execution of apoptosis, induction of ER stress, and inhibition of protein synthesis. At 5 to 50 µM, for example, sorafenib inhibited the proliferation of hepatocellular carcinoma cell lines; the degree of inhibition was dependent on pERK expression [10]. Exposure of human leukemia cells to 10 µM sorafenib produced cytotoxicity that involved inducing ER stress and generation of ROS [12].…”

Section: Discussionmentioning

confidence: 99%

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Ex vivo Effects of Sorafenib and Regorafenib on Murine Hepatocytes

Almarzooqi¹

2014

J Clin Toxicol

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Sorafenib and regorafenib are structurally-related small-molecular-weight inhibitors of cellular kinases. Regorafenib has a Boxed Warning stating: "Severe and sometimes fatal hepatotoxicity has been observed in clinical trials", while sorafenib is considered less hepatotoxic. This ex vivo study assessed the effects of sorafenib (2.5 and 50 µM) and regorafenib (5.0 and 50 µM) on liver structure, ultrastructure, cellular respiration (mitochondrial O 2 consumption), ATP, caspase activity, urea synthesis, and glutathione. Liver fragments from Taylor Outbred mice were incubated in Krebs-Henseleit buffer (continuously gassed with 95% O 2 :5% CO 2 ) with and without the drugs for 3 to 4 h. The presence of sorafenib or regorafenib had insignificant effects on liver structure, cellular respiration, ATP, caspase-3 activity, urea synthesis, and glutathione. At 3 h, liver histology with and without 2.5 µM sorafenib or 5.0 µM regorafenib was similar. Liver histology with 50 µM sorafenib was slightly worse than untreated tissue at 3 h, showing single hepatocyte necrosis and cellular disintegration. With 50 µM regorafenib, the histology was closely mirroring untreated tissue at 3 h. Similarly, caspase-3, caspase-9, cytochrome c, BAX and annexin A2 immunostains showed no significant drug effects at 4 h (2.5 µM sorafenib or 5.0 µM regorafenib). Electron microscopy revealed a more prominent loss of rough endoplasmic reticulum (rER) integrity with regorafenib treatment compared with sorafenib treatment. Thus, derangements in the rER were more prominent with regorafenib. Otherwise, the studied hepatic surrogate biomarkers did not distinguish between the two compounds.

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Phosphorylated ERK is a potential predictor of sensitivity to sorafenib when treating hepatocellular carcinoma: evidence from an in vitrostudy

Cited by 130 publications

References 20 publications

Peripheral blood neutrophil count as a prognostic factor for patients with hepatocellular carcinoma treated with sorafenib

Peripheral blood neutrophil count as a prognostic factor for patients with hepatocellular carcinoma treated with sorafenib

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

Ex vivo Effects of Sorafenib and Regorafenib on Murine Hepatocytes

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