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Abstract：
Background: Lenvatinib is the most common multitarget receptor tyrosine kinase inhibitor for the treatment of advanced hepatocellular carcinoma (HCC). Acquired resistance to lenvatinib is one of the major factors leading to the failure of HCC treatment, but the underlying mechanism has not been fully characterized. Methods: We established lenvatinib-resistant cell lines, cell-derived xenografts (CDXs) and patient-derived xenografts (PDXs) and obtained lenvatinib-resistant HCC tumor tissues for further study. Results: We found that ubiquitin-specific protease 14 (USP14) was significantly increased in lenvatinib-resistant HCC cells and tumors. Silencing USP14 significantly attenuated lenvatinib resistance in vitro and in vivo. Mechanistically, USP14 directly interacts with and stabilizes calcium- and integrin-binding protein 1 (CIB1) by reversing K48-linked proteolytic ubiquitination at K24, thus facilitating the P21-activated kinase 1 (PAK1)-ERK1/2 signaling axis. Moreover, in vivo adeno-associated virus 9 mediated transduction of CIB1 promoted lenvatinib resistance in PDXs, whereas CIB1 knockdown resensitized the response of PDXs to lenvatinib. Conclusions: These findings provide new insights into the role of CIB1/PAK1-ERK1/2 signaling in lenvatinib resistance in HCC. Targeting CIB1 and its pathways may be a novel pharmaceutical intervention for the treatment of lenvatinib-resistant HCC.
摘要：
背景：Lenvatinib是治疗晚期肝细胞癌（HCC）最常见的多靶点受体酪氨酸激酶抑制剂。对乐伐替尼的获得性耐药是导致HCC治疗失败的主要因素之一，但是潜在的机制还没有得到充分的描述。方法：我们建立了耐乐替尼细胞系，细胞源性异种移植物（CDXs）和患者源性异种移植物（PDXs），并获得了耐乐替尼耐药的HCC肿瘤组织进行进一步研究。结果：我们发现泛素特异性蛋白酶14（USP14）在耐乐替尼的HCC细胞和肿瘤中显着增加。沉默USP14在体外和体内显着减弱了lenvatinib耐药性。机械上,USP14通过逆转K24处的K48连接的蛋白水解泛素化直接与钙和整联蛋白结合蛋白1（CIB1）相互作用并使其稳定，从而促进P21激活的激酶1（PAK1）-ERK1/2信号轴。此外，体内腺相关病毒9介导的CIB1转导促进了PDXs的lenvatinib耐药性，其中CIB1敲低使PDX对乐伐替尼的反应重新敏感。结论：这些发现为CIB1/PAK1-ERK1/2信号传导在肝癌乐伐替尼耐药中的作用提供了新的见解。TargetingCIB1及其通路可能是治疗lenvatinib耐药HCC的一种新型药物干预措施。
