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      BH3-only protein expression determines hepatocellular carcinoma response to sorafenib-based treatment

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          Abstract

          Hepatocellular carcinoma (HCC) represents a global health challenge with limited therapeutic options. Anti-angiogenic immune checkpoint inhibitor-based combination therapy has been introduced for progressed HCC, but improves survival only in a subset of HCC patients. Tyrosine-kinase inhibitors (TKI) such as sorafenib represent an alternative treatment option but have only modest efficacy. Using different HCC cell lines and HCC tissues from various patients reflecting HCC heterogeneity, we investigated whether the sorafenib response could be enhanced by combination with pro-apoptotic agents, such as TNF-related apoptosis-inducing ligand (TRAIL) or the BH3-mimetic ABT-737, which target the death receptor and mitochondrial pathway of apoptosis, respectively. We found that both agents could enhance sorafenib-induced cell death which was, however, dependent on specific BH3-only proteins. TRAIL augmented sorafenib-induced cell death only in NOXA-expressing HCC cells, whereas ABT-737 enhanced the sorafenib response also in NOXA-deficient cells. ABT-737, however, failed to augment sorafenib cytotoxicity in the absence of BIM, even when NOXA was strongly expressed. In the presence of NOXA, BIM-deficient HCC cells could be in turn strongly sensitized for cell death induction by the combination of sorafenib with TRAIL. Accordingly, HCC tissues sensitive to apoptosis induction by sorafenib and TRAIL revealed enhanced NOXA expression compared to HCC tissues resistant to this treatment combination. Thus, our results suggest that BH3-only protein expression determines the treatment response of HCC to different sorafenib-based drug combinations. Individual profiling of BH3-only protein expression might therefore assist patient stratification to certain TKI-based HCC therapies.

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          Most cited references 74

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          Sorafenib in advanced hepatocellular carcinoma.

          No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo. (ClinicalTrials.gov number, NCT00105443.) 2008 Massachusetts Medical Society
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            Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma

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              Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial

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                Author and article information

                Contributors
                Bantel.Heike@mh-hannover.de
                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group UK (London )
                2041-4889
                26 July 2021
                26 July 2021
                August 2021
                : 12
                : 8
                Affiliations
                [1 ]GRID grid.10423.34, ISNI 0000 0000 9529 9877, Department of Gastroenterology, , Hepatology and Endocrinology, Hannover Medical School, ; Hannover, Germany
                [2 ]GRID grid.10423.34, ISNI 0000 0000 9529 9877, Department of Visceral and Transplantation Surgery, , Hannover Medical School, ; Hannover, Germany
                [3 ]GRID grid.452463.2, German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, ; Hannover, Germany
                [4 ]GRID grid.10423.34, ISNI 0000 0000 9529 9877, Department of Pathology, , Hannover Medical School, ; Hannover, Germany
                [5 ]GRID grid.502798.1, ISNI 0000 0004 0561 903X, Dr. Margarete-Fischer-Bosch Institute of Clinical Pharmacology, ; Stuttgart, Germany
                [6 ]GRID grid.10392.39, ISNI 0000 0001 2190 1447, Interfaculty Institute of Biochemistry, University of Tübingen, ; Tübingen, Germany
                [7 ]GRID grid.7497.d, ISNI 0000 0004 0492 0584, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), ; Heidelberg, Germany
                [8 ]GRID grid.10392.39, ISNI 0000 0001 2190 1447, Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, ; Tübingen, Germany
                Article
                4020
                10.1038/s41419-021-04020-z
                8313681
                34312366
                © The Author(s) 2021

                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/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft (German Research Foundation);
                Award ID: SFB/TR-209
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100005972, Deutsche Krebshilfe (German Cancer Aid);
                Award ID: 70111929
                Award Recipient :
                Categories
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                Custom metadata
                © The Author(s) 2021

                Cell biology

                cancer, diseases

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