Targeted inhibition of PDGFRA with avapritinib, markedly enhances lenvatinib efficacy in hepatocellular carcinoma in vitro and in vivo: clinical implications

作者：Bixing Zhao, Yang Zhou, Niangmei Cheng, Xiaoyuan Zheng, Geng Chen, Xin Qi, Xiangzhi Zhang, Fei Wang, Qiuyu Zhuang, Yehuda G. Assaraf, Xiaolong Liu, Yingchao Wang, Yongyi Zeng · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2025 · DOI：10.1186/s13046-025-03386-8 · 被引用次数：9 · 研究领域：Hepatocellular Carcinoma Treatment and Prognosis、Fibroblast Growth Factor Research、Liver physiology and pathology

BACKGROUND: 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. METHODS: 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. RESULTS: 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 sens...