Synergistic antitumor effect of histone deacetylase class IIa inhibitor with lenvatinib in hepatocellular carcinoma
Synergistic antitumor effect of histone deacetylase class IIa inhibitor with lenvatinib in hepatocellular carcinoma
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DOI：
10.1007/s12072-023-10484-2
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发表时间：
2023-02-04
影响因子：
6.6
通讯作者：
Kato, Junji
中科院分区：
文献类型：
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作者：
Ito, Ryo;Miyanishi, Koji;Kato, Junji
组蛋白脱乙酰酶(HDAC)I类和IIa在肝细胞癌中高表达，并与生存率降低有关。然而，临床使用的PAN和I类抑制剂有严重的不良反应。在本研究中，我们评价了IIa类HDAC抑制剂(HDACi)与伦瓦替尼(Lenvatinib)联合治疗肝癌的疗效和耐受性。方法与结果IIa类HDACi与Lenvatinib联合治疗对人肝癌细胞株具有协同抗肿瘤作用。在小鼠模型中，这种疗法显示出显著的抗肿瘤作用，并且几乎没有不良事件发生。免疫印迹显示成纤维细胞生长因子受体4(FGFR4)和成纤维细胞生长因子19(FGF19)在细胞株中高表达，显示出较强的抗肿瘤作用。此外，IIa类HDACi给药可降低FGFR4的表达。在小干扰RNA(SiRNA)分析中，敲除HDACⅡa亚型HDAC9可减少FGFR4的表达并诱导细胞凋亡。临床标本免疫组织化学显示FGFR4和HDAC9的阳性率分别为32%和84%，且所有FGFR4阳性的患者均为HDAC9阳性。结论IIa类HDACi和Lenvatinib联合治疗可通过下调FGFR4和阻断FGFR信号通路诱导FGFR4阳性肝癌细胞株的凋亡，具有协同抗肿瘤作用和安全性。这种联合疗法克服了传统疗法的问题，将有益于FGFR4阳性的肝细胞癌患者。
BackgroundHistone deacetylase (HDAC) class I and IIa are highly expressed in hepatocellular carcinoma (HCC) and associated with decreased survival. However, clinically used pan and class I inhibitors have serious adverse events. In this study, we assessed the antitumor effects and tolerability of class IIa HDAC inhibitor (HDACI) with lenvatinib, which is a standard therapy for HCC.Methods and resultCombination therapy with class IIa HDACI and lenvatinib exerted synergistic antitumor effect in human HCC cell lines. In mouse models, this therapy showed significant antitumor effects, and few adverse events occurred. In immunoblotting, the expression of fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) was high in cell lines that showed a high antitumor effect. In addition, class IIa HDACI administration decreased the expression of FGFR4. In the small interfering RNA (siRNA) analysis, knockdown of HDAC9, which is an isoform of HDAC class IIa, reduced the expression of FGFR4 and induced apoptosis. Immunohistochemistry of human clinical specimens showed a positivity rate of 32% for FGFR4 and 84% for HDAC9 in HCC, and all FGFR4-positive patients were HDAC9 positive.ConclusionClass IIa HDACI and lenvatinib combination therapy induces apoptosis by downregulating FGFR4 and blocking the FGFR signaling in FGFR4-positive HCC cell lines and has demonstrated synergistic antitumor effects and safety. This combination therapy overcomes the problems of conventional therapies and will be beneficial for FGFR4-positive HCC patients.