Therapeutic efficacy of FASN inhibition in preclinical models of HCC.
Therapeutic efficacy of FASN inhibition in preclinical models of HCC.
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DOI：
10.1002/hep.32359
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发表时间：
2022-10
期刊：
影响因子：
13.5
通讯作者：
Chen, Xin
中科院分区：
文献类型：
--
作者：
Wang, Haichuan;Zhou, Yi;Xu, Hongwei;Wang, Xue;Zhang, Yi;Shang, Runze;O'Farrell, Marie;Roessler, Stephanie;Sticht, Carsten;Stahl, Andreas;Evert, Matthias;Calvisi, Diego F.;Zeng, Yong;Chen, Xin
脂肪酸合成酶（FATCH）的异常激活是HCC发生发展过程中的主要代谢事件。我们评估了TVB 3664，一种新型的Festival抑制剂，单独或联合治疗HCC的疗效。在人HCC细胞系和多种癌基因驱动的HCC小鼠模型中评估了TVB 3664单独或与酪氨酸激酶抑制剂或检查点抑制剂抗PD-L1抗体联合治疗的疗效和靶向分子途径。进行RNAseq以阐明TVB 3664对整体基因表达和肿瘤代谢的影响。TVB 3664显著改善老年小鼠的脂肪肝表型和AKT诱导的肝脂肪变性。TVB 3664单药治疗在由PTEN和c-MET过表达缺失诱导的NASH相关小鼠HCC中显示出中等疗效。TVB 3664与卡博替尼组合在该鼠模型中触发肿瘤消退，但没有改善对免疫疗法的响应性。整体基因表达显示，TVB 3664主要调节代谢过程，而TVB 3664与卡博替尼协同下调多种癌症相关途径，特别是AKT/mTOR途径和细胞增殖基因。TVB 3664还改善了索拉非尼和卡博替尼在FASN依赖性c-MYC驱动的HCC模型中的疗效。然而，TVB 3664在FASN非依赖性小鼠HCC模型中没有疗效或协同作用。这项临床前研究表明，靶向FRENTA作为HCC治疗的单一疗法的疗效有限。然而，Festival抑制剂可以与其他药物联合使用，以提高疗效。这些联合疗法可以基于驱动癌基因开发，支持HCC治疗的精确医学方法。
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.
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影响因子：
13.5
作者：
Qiao, Yu;Wang, Jingxiao;Chen, Xin
通讯作者：
Chen, Xin
影响因子：
11.1
作者：
Ventura R;Mordec K;Waszczuk J;Wang Z;Lai J;Fridlib M;Buckley D;Kemble G;Heuer TS
通讯作者：
Heuer TS
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
DOI：
10.1016/j.bbrc.2015.08.055
发表时间：
2015-09-25
影响因子：
3.1
作者：
Saini, Nipun;Black, Paul N.;DiRusso, Concetta C.
通讯作者：
DiRusso, Concetta C.
影响因子：
24.5
作者：
Senni, Nadia;Savall, Mathilde;Bossard, Pascale
通讯作者：
Bossard, Pascale