Comprehensive network analysis of the molecular mechanisms associated with sorafenib resistance in hepatocellular carcinoma

Lin, Hui‐Ping; Zhang, Rui; Wu, Wenrui; Lei, Liming

doi:10.1016/j.cancergen.2020.04.076

Cited by 9 publications

(11 citation statements)

References 63 publications

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“…In accordance with our findings, the identification of genes and signaling pathways related to sorafenib resistance has also been found using bioinformatics methods in several studies[ 44 , 102 , 103 ]. Using the web tool GEO2R, GSE73571, and GSE109211 datasetwere analyzed.…”

Section: Discussionsupporting

confidence: 91%

“…164 sorafenib resistance-related DEGs (121 upregulated and 43 downregulated in sorafenib resistant samples compared sorafenib sensitive ones) were identified and nine hub genes were confirmed as key genes from the GSE109211 dataset [ 44 ]. In another study on the identification of microRNAs and transcription factors related to sorafenib resistance, GSE73571 was used and 827 significant DEGs were obtained using the “limma” package of R language [ 102 ].…”

Section: Discussionmentioning

confidence: 99%

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Integrated Transcriptomic Analysis Revealed Hub Genes and Pathways Involved in Sorafenib Resistance in Hepatocellular Carcinoma

Jiang¹,

Zhang²,

Li³

et al. 2021

Pathol. Oncol. Res.

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Hepatocellular carcinoma (HCC), a high mortality malignancy, has become a worldwide public health concern. Acquired resistance to the multikinase inhibitor sorafenib challenges its clinical efficacy and the survival benefits it provides to patients with advanced HCC. This study aimed to identify critical genes and pathways associated with sorafenib resistance in HCC using integrated bioinformatics analysis. Differentially expressed genes (DEGs) were identified using four HCC gene expression profiles (including 34 sorafenib-resistant and 29 sorafenib-sensitive samples) based on the robust rank aggregation method and R software. Gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) online tool. A protein–protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes (STRING), and small molecules reversing sorafenib resistance were searched for using the connectivity map (CMAP) database. Pearson correlation and survival analyses of hub genes were performed using cBioPortal and Gene Expression Profiling and Interactive Analysis (GEPIA). Finally, the expression levels of hub genes in sorafenib-resistant HCC cells were verified using quantitative polymerase chain reaction (q-PCR). A total of 165 integrated DEGs (66 upregulated and 99 downregulated in sorafenib resistant samples compared sorafenib sensitive ones) primarily enriched in negative regulation of endopeptidase activity, extracellular exosome, and protease binding were identified. Some pathways were commonly shared between the integrated DEGs. Seven promising therapeutic agents and 13 hub genes were identified. These findings provide a strategy and theoretical basis for overcoming sorafenib resistance in HCC patients.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Integrated Transcriptomic Analysis Revealed Hub Genes and Pathways Involved in Sorafenib Resistance in Hepatocellular Carcinoma

Jiang¹,

Zhang²,

Li³

et al. 2021

Pathol. Oncol. Res.

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“…The primary endpoints were safety and tolerability with 12 patients (25%) demonstrating grade ≥3 adverse events. The objective response rate (ORR) was 20% (95%CI [15][16][17][18][19][20][21][22][23][24][25][26] in patients treated with 3 mg/kg of nivolumab. However, confirmatory phase III study checkmate 459 enrolled 743 treatment-naïve patients with advanced HCC and observed no significant difference in overall survival between nivolumab and sorafenib with an OS of 16.4 months in the experimental arm vs. 14.7 months in the control group (HR 0.85; 95%CI 0.72-1.02, p = 0.0752) [8].…”

Section: Current Molecular Targets Of Approved Systemic Agentsmentioning

confidence: 99%

“…Collectively, 72% of tumors analyzed were identified to have aberrations in either one of these signaling pathways. Aberrations within CDK1 and CDKN1A, important modulators of the cell cycle, may predict resistance to treatment with sorafenib [23]; deficiency of FBXW7, a suppressor, has been associated with increased radio sensitivity in HCC [24].…”

Section: Cell Cycle Signalingmentioning

confidence: 99%

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Molecular Targets, Pathways, and Therapeutic Implications for Hepatocellular Carcinoma

Gong

Chuang

Cho

et al. 2020

IJMS

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Hepatocellular carcinoma (HCC) represents one of the leading causes of cancer mortality worldwide. While significant advances have been made for the treatment of advanced hepatocellular carcinoma in the past few years, the prognosis remains poor and effective biomarkers to guide selection of therapies remain noticeably absent. However, several targeted therapies have been approved in the past few years that have improved the outlook for this disease. In this review, we will highlight the recent therapies approved for the treatment of advanced HCC and discuss promising therapeutic options, targets, and pathways for drug development and consideration for future clinical trials.

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Mechanisms of Pharmacoresistance in Hepatocellular Carcinoma: New Drugs but Old Problems

et al. 2021

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Hepatocellular carcinoma (HCC) is a malignancy with poor prognosis when diagnosed at advanced stages in which curative treatments are no longer applicable. A small group of these patients may still benefit from transarterial chemoembolization. The only therapeutic option for most patients with advanced HCC is systemic pharmacological treatments based on tyrosine kinase inhibitors (TKIs) and immunotherapy. Available drugs only slightly increase survival, as tumor cells possess additive and synergistic mechanisms of pharmacoresistance (MPRs) prior to or enhanced during treatment. Understanding the molecular basis of MPRs is crucial to elucidate the genetic signature underlying HCC resistome. This will permit the selection of biomarkers to predict drug treatment response and identify tumor weaknesses in a personalized and dynamic way. In this article, we have reviewed the role of MPRs in current first-line drugs and the combinations of immunotherapeutic agents with novel TKIs being tested in the treatment of advanced HCC.

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Comprehensive network analysis of the molecular mechanisms associated with sorafenib resistance in hepatocellular carcinoma

Cited by 9 publications

References 63 publications

Integrated Transcriptomic Analysis Revealed Hub Genes and Pathways Involved in Sorafenib Resistance in Hepatocellular Carcinoma

Integrated Transcriptomic Analysis Revealed Hub Genes and Pathways Involved in Sorafenib Resistance in Hepatocellular Carcinoma

Molecular Targets, Pathways, and Therapeutic Implications for Hepatocellular Carcinoma

Mechanisms of Pharmacoresistance in Hepatocellular Carcinoma: New Drugs but Old Problems

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