Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225009, China.
Int J Biol Sci. 2024 Jun 3;20(9):3269-3284. doi: 10.7150/ijbs.96031. eCollection 2024.
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. 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. We found that ubiquitin-specific protease 14 (USP14) was significantly increased in lenvatinib-resistant HCC cells and tumors. Silencing USP14 significantly attenuated lenvatinib resistance and . 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, adeno-associated virus 9 mediated transduction of CIB1 promoted lenvatinib resistance in PDXs, whereas CIB1 knockdown resensitized the response of PDXs to lenvatinib. 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.
仑伐替尼是治疗晚期肝细胞癌（HCC）最常用的多靶点受体酪氨酸激酶抑制剂。仑伐替尼耐药是导致 HCC 治疗失败的主要因素之一，但潜在的机制尚未完全阐明。我们建立了仑伐替尼耐药细胞系、细胞衍生的异种移植瘤（CDX）和患者衍生的异种移植瘤（PDX），并获得了仑伐替尼耐药 HCC 肿瘤组织进行进一步研究。我们发现，泛素特异性蛋白酶 14（USP14）在仑伐替尼耐药 HCC 细胞和肿瘤中显著增加。沉默 USP14 显著减弱了仑伐替尼耐药性，并。在机制上，USP14 通过逆转 K24 上的 K48 连接的蛋白水解泛素化，直接与钙和整合素结合蛋白 1（CIB1）相互作用并稳定 CIB1，从而促进 P21 激活激酶 1（PAK1）-ERK1/2 信号通路。此外，腺相关病毒 9 介导的 CIB1 转导促进了 PDX 中的仑伐替尼耐药性，而 CIB1 敲低使 PDX 对仑伐替尼的反应重新敏感。这些发现为 CIB1/PAK1-ERK1/2 信号通路在 HCC 中仑伐替尼耐药中的作用提供了新的见解。靶向 CIB1 及其途径可能是治疗仑伐替尼耐药 HCC 的一种新的药物干预策略。
