PDF(Pubmed)
Abstract：
Lenvatinib, a multi-kinase inhibitor, serves a crucial role in the treatment of unresectable hepatocellular carcinoma (HCC). However, >50% of patients receiving lenvatinib therapy experience tumor growth or metastasis within 1 year, highlighting the need to address acquired resistance as a critical clinical challenge. To elucidate the factors associated with acquired resistance to lenvatinib, a lenvatinib-resistant HCC cell line (JHH-7_LR) was established by exposing a lenvatinib-sensitive HCC cell line, JHH-7, to lenvatinib. The changes in protein expression associated with the development of resistance were analyzed using a proteomic approach, detecting 1,321 proteins and significant changes in the expression of 267 proteins. Using Ingenuity Pathway Analysis bioinformatics software, it was revealed that the activity of multiple signaling pathways varied alongside the changes in expression of these proteins, and c-SRC was identified as a protein involved in a number of these signaling pathways, with its activity varying markedly upon the acquisition of resistance. When co-administering dasatinib, a c-SRC inhibitor, the partial restoration of lenvatinib sensitivity in the JHH-7_LR cell line was observed. The present study demonstrated that increased c-SRC expression was partially associated with HCC resistance to lenvatinib, suggesting that c-SRC inhibition could reduce the resistance of HCC to lenvatinib.
摘要：
Lenvatinib,一种多激酶抑制剂，在不可切除的肝细胞癌（HCC）的治疗中起着至关重要的作用。然而,>50%接受乐伐替尼治疗的患者在1年内经历肿瘤生长或转移，强调需要解决获得性耐药作为一个关键的临床挑战。为了阐明与来伐替尼获得性耐药相关的因素，通过暴露对lenvatinib敏感的HCC细胞系建立了对lenvatinib耐药的HCC细胞系（JHH-7_LR），JHH-7，来伐替尼。使用蛋白质组学方法分析了与抗性发展相关的蛋白质表达的变化，检测1,321种蛋白和267种蛋白表达的显著变化。使用创造性途径分析生物信息学软件，研究表明，多个信号通路的活性随着这些蛋白质表达的变化而变化，c-SRC被鉴定为参与许多这些信号通路的蛋白质，其活性随着抗性的获得而显著变化。当共同使用达沙替尼时，c-SRC抑制剂,在JHH-7_LR细胞系中观察到lenvatinib敏感性的部分恢复。本研究表明，c-SRC表达增加与肝癌对乐伐替尼的耐药性部分相关，表明c-SRC抑制可以降低肝癌对乐伐替尼的耐药性。
