Research Papers:

Antitumor effects of regorafenib and sorafenib in preclinical models of hepatocellular carcinoma

Maria Kissel, Sandra Berndt, Lukas Fiebig, Simon Kling, Qunsheng Ji, Qingyang Gu, Tina Lang, Frank-Thorsten Hafner, Michael Teufel and Dieter Zopf _

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Oncotarget. 2017; 8:107096-107108. https://doi.org/10.18632/oncotarget.22334

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Maria Kissel1, Sandra Berndt2, Lukas Fiebig1, Simon Kling3, Qunsheng Ji4, Qingyang Gu4, Tina Lang5, Frank-Thorsten Hafner1, Michael Teufel6 and Dieter Zopf2

1Drug Discovery, Bayer AG, Wuppertal, Germany

2Drug Discovery, Bayer AG, Berlin, Germany

3Biochemistry, NMI Natural and Medicinal Sciences Institute, University of Tübingen, Reutlingen, Germany

4Research Service Division, Oncology & Immunology Unit, WuXi AppTec Co. Ltd., Shanghai, China

5Research & Clinical Sciences Statistics, Bayer AG, Berlin, Germany

6Translational Medicine Oncology, Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA

Correspondence to:

Dieter Zopf, email: [email protected]

Keywords: regorafenib; sorafenib; HCC; antitumor activity; preclinical pharmacology

Received: June 08, 2017     Accepted: September 20, 2017     Published: November 06, 2017


The purpose of this study was to investigate the antitumor activity of regorafenib and sorafenib in preclinical models of HCC and to assess their mechanism of action by associated changes in protein expression in a HCC-PDX mouse model. Both drugs were administered orally once daily at 10 mg/kg (regorafenib) or 30 mg/kg (sorafenib), which recapitulate the human exposure at the maximally tolerated dose in mice.

In a H129 hepatoma model, survival times differed significantly between regorafenib versus vehicle (p=0.0269; median survival times 36 vs 27 days), but not between sorafenib versus vehicle (p=0.1961; 33 vs 28 days). Effects on tumor growth were assessed in 10 patient-derived HCC xenograft (HCC-PDX) models. Significant tumor growth inhibition was observed in 8/10 models with regorafenib and 7/10 with sorafenib; in four models, superior response was observed with regorafenib versus sorafenib which was deemed not to be due to lower sorafenib exposure. Bead-based multiplex western blot analysis was performed with total protein lysates from drug- and vehicle-treated HCC-PDX xenografts. Protein expression was substantially different in regorafenib- and sorafenib-treated samples compared with vehicle. The pattern of upregulated proteins was similar with both drugs and indicates an activated RAF/MEK/ERK pathway, but more proteins were downregulated with sorafenib versus regorafenib. Overall, both regorafenib and sorafenib were effective in mouse models of HCC, although several cases showed better regorafenib activity which may explain the observed efficacy of regorafenib in sorafenib-refractory patients.

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