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      The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects

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          Abstract

          Sorafenib is a multikinase inhibitor capable of facilitating apoptosis, mitigating angiogenesis and suppressing tumor cell proliferation. In late-stage hepatocellular carcinoma (HCC), sorafenib is currently an effective first-line therapy. Unfortunately, the development of drug resistance to sorafenib is becoming increasingly common. This study aims to identify factors contributing to resistance and ways to mitigate resistance. Recent studies have shown that epigenetics, transport processes, regulated cell death, and the tumor microenvironment are involved in the development of sorafenib resistance in HCC and subsequent HCC progression. This study summarizes discoveries achieved recently in terms of the principles of sorafenib resistance and outlines approaches suitable for improving therapeutic outcomes for HCC patients.

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          Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial.

          Andrew Zhu, Joon Park, Baek-Yeol Ryoo … (2015)
          VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib.
          Article 0 comments Cited 328 times – based on 0 reviews     Review now
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            Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis.

            Xiaofang Sun, Xiaohua Niu, Ruochan Chen … (2016)
            Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide and currently has the fastest rising incidence of all cancers. Sorafenib was originally identified as an inhibitor of multiple oncogenic kinases and remains the only approved systemic therapy for advanced HCC. However, acquired resistance to sorafenib has been found in HCC patients, which results in poor prognosis. Here, we show that metallothionein (MT)-1G is a critical regulator and promising therapeutic target of sorafenib resistance in human HCC cells. The expression of MT-1G messenger RNA and protein is remarkably induced by sorafenib but not other clinically relevant kinase inhibitors (e.g., erlotinib, gefitinib, tivantinib, vemurafenib, selumetinib, imatinib, masitinib, and ponatinib). Activation of the transcription factor nuclear factor erythroid 2-related factor 2, but not p53 and hypoxia-inducible factor 1-alpha, is essential for induction of MT-1G expression following sorafenib treatment. Importantly, genetic and pharmacological inhibition of MT-1G enhances the anticancer activity of sorafenib in vitro and in tumor xenograft models. The molecular mechanisms underlying the action of MT-1G in sorafenib resistance involve the inhibition of ferroptosis, a novel form of regulated cell death. Knockdown of MT-1G by RNA interference increases glutathione depletion and lipid peroxidation, which contributes to sorafenib-induced ferroptosis.
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              Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib.

              Jean-Claude Mazière, Zakaria Ezzoukhry, Bruno Chauffert … (2013)
              The multikinase inhibitor sorafenib is currently the treatment of reference for advanced hepatocellular carcinoma (HCC). In our report, we examined the cytotoxic effects of sorafenib on HCC cells. We report that the depletion of the intracellular iron stores achieved by using the iron chelator deferoxamine (DFX) strikingly protects HCC cells from the cytotoxic effects of sorafenib. The protective effect of the depletion of intracellular iron stores could not be explained by an interference with conventional forms of programmed cell death, such as apoptosis or autophagic cell death. We also found that DFX did not prevent sorafenib from reaching its intracellular target kinases. Instead, the depletion of intracellular iron stores prevented sorafenib from inducing oxidative stress in HCC cells. We examined the possibility that sorafenib might exert a cytotoxic effect that resembles ferroptosis, a form of cell death in which iron-dependent oxidative mechanisms play a pivotal role. In agreement with this possibility, we found that pharmacological inhibitors (ferrostatin-1) and genetic procedures (RNA interference against IREB-2) previously reported to modulate ferroptosis, readily block the cytotoxic effects of sorafenib in HCC cells. Collectively, our findings identify ferroptosis as an effective mechanism for the induction of cell death in HCC. Ferroptosis could potentially become a goal for the medical treatment of HCC, thus opening new avenues for the optimization of the use of sorafenib in these tumors. © 2013 UICC.
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                Author and article information

                Contributors
                F. P. Reiter: Florian.Reiter@med.uni-muenchen.de
                E. N. De Toni: Enrico.deToni@med.uni-muenchen.de
                Xuehao Wang: wangxh@njmu.edu.cn
                Journal
                Journal ID (nlm-ta): Signal Transduct Target Ther
                Journal ID (iso-abbrev): Signal Transduct Target Ther
                Title: Signal Transduction and Targeted Therapy
                Publisher: Nature Publishing Group UK (London )
                ISSN (Print): 2095-9907
                ISSN (Electronic): 2059-3635
                Publication date (Electronic): 10 June 2020
                Publication date PMC-release: 10 June 2020
                Publication date Collection: 2020
                Volume: 5
                Electronic Location Identifier: 87
                Affiliations
                [1 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, Department of General Surgery, Nanjing First Hospital, , Nanjing Medical University, ; Nanjing, China
                [2 ]GRID grid.477246.4, Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, , Chinese Academy of Medical Sciences, ; Nanjing, China
                [3 ]GRID grid.412676.0, ISNI 0000 0004 1799 0784, Department of Gastroenterology, , The First Affiliated Hospital of Nanjing Medical University, ; Nanjing, China
                [4 ]GRID grid.25073.33, ISNI 0000 0004 1936 8227, Michael G. DeGroote School of Medicine, , McMaster University, ; Hamilton, ON Canada
                [5 ]GRID grid.412676.0, ISNI 0000 0004 1799 0784, Department of Radiology, , The First Affiliated Hospital of Nanjing Medical University, ; Nanjing, China
                [6 ]Department of Medicine II, University Hospital, LMU, Munich, Germany
                [7 ]Liver Center Munich, University Hospital, LMU, Munich, Germany
                Author information
                http://orcid.org/0000-0003-1828-434X
                Article
                Publisher ID: 187
                DOI: 10.1038/s41392-020-0187-x
                PMC ID: 7292831
                PubMed ID: 32532960
                SO-VID: 47496f41-e1c3-48ae-a76c-79a68b29652a
                Copyright © © The Author(s) 2020
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 13 January 2020
                Date revision received : 14 March 2020
                Date accepted : 26 April 2020
                Funding
                Funded by: National Natural Science Foundation of China| key program. Grant No.81530048
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 81902485
                Award Recipient :
                Categories
                Subject: Review Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2020

                Keywords: drug development,gastrointestinal cancer
                Data availability:
                Keywords: drug development, gastrointestinal cancer

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