He Yuchao, Liu Dongming, Ling Aomei, Han Zhiqiang, Cui Jinfang, Cheng Jinghui, Feng Yuanying, Liu Wei, Gong Wenchen, Xia Yuren, Chen Liwei, Luo Yi, Wang Yu, Tian Xiangdong, Wu Qiang, Chen Lu, Guo Hua
Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
Cell Death Dis. 2025 Jul 1;16(1):466. doi: 10.1038/s41419-025-07789-5.
Hepatocellular carcinoma (HCC) poses a major global health challenge owing to limited treatment efficacy and drug resistance to therapies such as the tyrosine kinase inhibitor (TKI) sorafenib. We utilized a microfluidic three-dimensional (3D) drug testing system to assess drug responses in 37 fresh clinical samples and performed immunohistochemical analysis of 41 tumor tissue samples that received sorafenib therapy. Results revealed that Wnt/β-catenin activation was associated with sorafenib resistance, with higher nuclear β-catenin levels predicting poor response. Targeting Wnt/β-catenin via genetic intervention enhanced TKI sensitivity by promoting apoptosis and reducing clonogenicity. Through a large scale of drug and inhibitor library screening, we identified PRI-724, a potent CREB-binding protein (CBP)/β-catenin transcription antagonist, which synergistically induces apoptosis with sorafenib in vitro and in vivo by inhibiting β-catenin/CBP/c-myc, β-catenin nuclear localization and ERK/AKT signaling. The microfluidic 3D drug testing system confirmed the synergistic anti-tumor effects of this combination, underscoring its clinical application potential. Conclusively, our study provides a new combination therapy with sorafenib and PRI-724 to overcome TKI resistance and improve clinical outcomes in patients with HCC. Schematic representation of the speculative molecular mechanism model. Our study revealed that β-catenin activation drives sorafenib resistance in HCC, and disrupting β-catenin enhances sorafenib efficacy by promoting apoptosis and inhibiting proliferation. The combination of sorafenib and PRI-724, a Wnt/β-catenin inhibitor, showed synergistic anti-tumor effects in vitro across various HCC cell lines, in vivo using xenograft models, ex vivo utilizing MDT chip system to explore clinical applications, offering a novel therapeutic strategy for HCC patients.
由于治疗效果有限以及对酪氨酸激酶抑制剂（TKI）索拉非尼等疗法存在耐药性，肝细胞癌（HCC）构成了一项重大的全球健康挑战。我们利用微流控三维（3D）药物测试系统评估了37份新鲜临床样本中的药物反应，并对41份接受索拉非尼治疗的肿瘤组织样本进行了免疫组织化学分析。结果显示，Wnt/β-连环蛋白激活与索拉非尼耐药相关，细胞核β-连环蛋白水平较高预示着反应不佳。通过基因干预靶向Wnt/β-连环蛋白可通过促进细胞凋亡和降低克隆形成能力来增强TKI敏感性。通过大规模的药物和抑制剂文库筛选，我们鉴定出PRI-724，一种有效的CREB结合蛋白（CBP）/β-连环蛋白转录拮抗剂，它在体外和体内通过抑制β-连环蛋白/CBP/c-myc、β-连环蛋白核定位以及ERK/AKT信号传导，与索拉非尼协同诱导细胞凋亡。微流控3D药物测试系统证实了这种联合疗法的协同抗肿瘤作用，突出了其临床应用潜力。总之，我们的研究提供了一种索拉非尼与PRI-724的新联合疗法，以克服TKI耐药性并改善HCC患者的临床结局。推测分子机制模型的示意图。我们的研究表明，β-连环蛋白激活驱动HCC中的索拉非尼耐药，破坏β-连环蛋白可通过促进细胞凋亡和抑制增殖来增强索拉非尼疗效。索拉非尼与Wnt/β-连环蛋白抑制剂PRI-724的联合在体外对各种HCC细胞系、在体内使用异种移植模型以及在体外利用MDT芯片系统探索临床应用时均显示出协同抗肿瘤作用，为HCC患者提供了一种新的治疗策略。
