机构：[1]Liver Transplantation Division, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.四川大学华西医院[2]Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA.[3]Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.四川大学华西医院[4]Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China.[5]Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, California, USA.[6]Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.[7]3-V Biosciences, Menlo Park, CA, USA.[8]Institute of Pathology, Heidelberg University, Heidelberg, Germany.[9]NGS Core Facility, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.[10]Institute of Pathology, University of Regensburg, Regensburg, Germany.
Aberrant activation of fatty acid synthase (FASN) is a major metabolic event during the development of HCC. We evaluated the therapeutic efficacy of TVB3664, a novel FASN inhibitor, either alone or in combination, for HCC treatment.The therapeutic efficacy and the molecular pathways targeted by TVB3664, either alone or with tyrosine kinase inhibitors or the checkpoint inhibitor anti-PD-L1 antibody, were assessed in human HCC cell lines and multiple oncogene-driven HCC mouse models. RNAseq was performed to elucidate the effects of TVB3664 on global gene expression and tumor metabolism. TVB3664 significantly ameliorated the fatty liver phenotype in the aged mice and AKT-induced hepatic steatosis. TVB3664 monotherapy showed moderate efficacy in NASH-related murine HCCs, induced by loss of PTEN and c-MET overexpression. TVB3664, in combination with cabozantinib, triggered tumor regression in this murine model but did not improve the responsiveness to immunotherapy. Global gene expression revealed that TVB3664 predominantly modulated metabolic processes, while TVB3664 synergized with cabozantinib to downregulate multiple cancer-related pathways, especially the AKT/mTOR pathway and cell proliferation genes. TVB3664 also improved the therapeutic efficacy of sorafenib and cabozantinib in the FASN-dependent c-MYC-driven HCC model. However, TVB3664 had no efficacy nor synergistic effects in FASN-independent murine HCC models.This preclinical study suggests the limited efficacy of targeting FASN as monotherapy for HCC treatment. However, FASN inhibitors could be combined with other drugs for improved effectiveness. These combination therapies could be developed based on the driver oncogenes, supporting precision medicine approaches for HCC treatment.This article is protected by copyright. All rights reserved.
基金：
This study was supported by NIH grants R01CA204586, R01CA239251,
R01CA250227 and R03CA288375 to XC, P30DK026743 for UCSF Liver Center; National Natural
Science Foundation (82002967) to HW. SR was supported by funds from German Cancer Aid
(Deutsche Krebshilfe, project no. 70113922) and European Union's Horizon 2020 research and
innovation programme under Eurostars (grant E! 113707, LiverQR).
第一作者机构：[1]Liver Transplantation Division, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.[2]Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA.[3]Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
通讯作者：
通讯机构：[1]Liver Transplantation Division, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.[2]Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA.[10]Institute of Pathology, University of Regensburg, Regensburg, Germany.[*1]Institute of Pathology, University of Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany[*2]Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan 610041, China.[*3]Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143, USA. E-mail:
推荐引用方式(GB/T 7714)：
Wang Haichuan,Zhou Yi,Xu Hongwei,et al.Therapeutic efficacy of FASN inhibition in preclinical models of HCC.[J].HEPATOLOGY.2022,76(4):951-966.doi:10.1002/hep.32359.
APA：
Wang Haichuan,Zhou Yi,Xu Hongwei,Wang Xue,Zhang Yi...&Chen Xin.(2022).Therapeutic efficacy of FASN inhibition in preclinical models of HCC..HEPATOLOGY,76,(4)
MLA：
Wang Haichuan,et al."Therapeutic efficacy of FASN inhibition in preclinical models of HCC.".HEPATOLOGY 76..4(2022):951-966
医学