Zhao Bixing, Zhou Yang, Cheng Niangmei, Zheng Xiaoyuan, Chen Geng, Qi Xin, Zhang Xiangzhi, Wang Fei, Zhuang Qiuyu, Assaraf Yehuda G, Liu Xiaolong, Wang Yingchao, Zeng Yongyi
The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, P. R. China.
Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, P. R. China.
J Exp Clin Cancer Res. 2025 May 7;44(1):139. doi: 10.1186/s13046-025-03386-8.
Lenvatinib, a tyrosine kinase receptor inhibitor, has emerged as a frontline therapeutic strategy for the management of advanced hepatocellular carcinoma (HCC). However, the modest response rate observed with lenvatinib and the rapid emergence of chemoresistance highlight the urgent need to elucidate the underlying molecular mechanisms. Herein we aimed at identifying the molecular mechanisms underlying lenvatinib resistance in HCC and investigated the efficacy of targeted combination therapies to surmount this chemoresistance.
We utilized CRISPR/Cas9 gene knockout screening combined with transcriptome sequencing of lenvatinib-resistant HCC cell lines to identify resistance-associated genes. PDGFRA overexpression was validated in human lenvatinib-resistant HCC cells. We further corroborated the in vitro and in vivo role of PDGFRA in lenvatinib resistance using a PDGFRA inhibitor, avapritinib, employing a mouse orthotopic HCC model, patient-derived organoids (PDO), and patient-derived xenografts (PDX). The association between PDGFRA expression and patient prognosis was also assessed. Mechanistic studies were conducted to elucidate the signaling pathways contributing to lenvatinib resistance mediated by PDGFRA.
PDGFRA overexpression was identified as a key determinant of lenvatinib-resistance in HCC cells. Consistently, ectopic PGDGFRA overexpression conferred lenvatinib resistance upon HCC cells. Treatment with the PDGFRA inhibitor avapritinib sensitized HCC cells to lenvatinib in mouse orthotopic HCC, PDO, and PDX models. Increased PDGFRA expression was correlated with poor prognosis in HCC patients. Mechanistic studies revealed that lenvatinib treatment or PDGFRA overexpression promoted HCC resistance through the PTEN/AKT/GSK-3β/β-catenin signaling pathway.
Our findings demonstrate that PDGFRA overexpression mediates lenvatinib resistance in HCC and that targeting PDGFRA with avapritinib, surmounts this resistance. Furthermore, the PTEN/AKT/GSK-3β/β-catenin pathway was implicated in lenvatinib resistance, providing a potential therapeutic strategy for HCC patients displaying lenvatinib resistance. Further clinical studies are warranted to validate these findings and to explore the clinical application of PDGFRA-targeted therapies in HCC treatment.
乐伐替尼是一种酪氨酸激酶受体抑制剂，已成为晚期肝细胞癌（HCC）治疗的一线策略。然而，乐伐替尼观察到的适度反应率以及化疗耐药性的迅速出现凸显了迫切需要阐明其潜在分子机制。在此，我们旨在确定HCC中乐伐替尼耐药的分子机制，并研究靶向联合治疗克服这种化疗耐药性的疗效。
我们利用CRISPR/Cas9基因敲除筛选结合乐伐替尼耐药HCC细胞系的转录组测序来鉴定耐药相关基因。在人乐伐替尼耐药HCC细胞中验证了血小板衍生生长因子受体A（PDGFRA）的过表达。我们使用PDGFRA抑制剂阿伐替尼，通过小鼠原位HCC模型、患者来源类器官（PDO）和患者来源异种移植瘤（PDX），进一步证实了PDGFRA在乐伐替尼耐药中的体内外作用。还评估了PDGFRA表达与患者预后之间的关联。进行机制研究以阐明由PDGFRA介导的导致乐伐替尼耐药的信号通路。
PDGFRA过表达被确定为HCC细胞中乐伐替尼耐药的关键决定因素。同样，异位PDGFRA过表达赋予HCC细胞乐伐替尼耐药性。在小鼠原位HCC、PDO和PDX模型中，用PDGFRA抑制剂阿伐替尼治疗使HCC细胞对乐伐替尼敏感。PDGFRA表达增加与HCC患者的不良预后相关。机制研究表明，乐伐替尼治疗或PDGFRA过表达通过磷脂酰肌醇-3-激酶的磷酸酶和张力蛋白同源物（PTEN）/蛋白激酶B（AKT）/糖原合成酶激酶-3β（GSK-3β）/β-连环蛋白信号通路促进HCC耐药。
我们的研究结果表明，PDGFRA过表达介导HCC中的乐伐替尼耐药，而用阿伐替尼靶向PDGFRA可克服这种耐药性。此外，PTEN/AKT/GSK-3β/β-连环蛋白通路与乐伐替尼耐药有关，为显示乐伐替尼耐药的HCC患者提供了一种潜在的治疗策略。需要进一步的临床研究来验证这些发现，并探索PDGFRA靶向治疗在HCC治疗中的临床应用。
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