Cheng Tzu-Chun, Huang Bu-Miin, Liao You-Cheng, Chang Han-Sheng, Tu Shih-Hsin, Ho Yuan-Soon, Chen Li-Ching
Institute of Biochemistry and Molecular Biology, College of Life Sciences, China Medical University, Taichung, Taiwan.
Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Int J Cancer. 2025 Apr 15;156(8):1606-1620. doi: 10.1002/ijc.35271. Epub 2024 Dec 16.
Breast cancer is the most common cancer among women. Among them, human epidermal growth factor receptor-positive (HER2+) breast cancer is more malignant. Fortunately, many anti-HER2 drugs are currently used in clinical treatments to increase patient survival. However, some HER2+ patients (~15%) still develop drug resistance after receiving trastuzumab treatment, leading to treatment failure. Using CCLE and METABRIC database analyses, we found that fibroblast growth factor receptor 4 (FGFR4) mRNA was highly detected in tumors from HER2+ breast cancer patients (p < .001) and was associated with poorer survival in breast cancer patients. Through retrospective immunohistochemical staining analysis, we detected higher expression of FGFR4 protein in breast cancer tissues collected from patients who were resistant to trastuzumab therapy compared with breast cancer patients who responded to treatment. An FGFR4 inhibitor (FGF401) effectively inhibits tumor growth in trastuzumab-insensitive patient-derived xenograft (PDX) tumor-bearing mice. For molecular mechanism studies, we demonstrated that HER2/FGFR4 protein complexes were detected on the cell membrane of the tumor tissues in these trastuzumab-insensitive PDX tumor tissues. After trastuzumab treatment in these drug-resistant breast cancer cells, FGFR4 translocates and enters the nucleus. However, trastuzumab-induced nuclear translocation of FGFR4/HER2-intracellular domain protein complex in trastuzumab-resistant cancer cells is blocked by FGF401 treatment. We believe that FGFR4 overexpression and complex formation with HER2 can serve as molecular markers to assist clinicians in identifying trastuzumab-resistant tumors. Our results suggest that FGF401 combined with trastuzumab as adjuvant therapy for patients with trastuzumab-resistant breast cancer may be a potential new treatment strategy.
乳腺癌是女性中最常见的癌症。其中，人表皮生长因子受体阳性（HER2+）乳腺癌的恶性程度更高。幸运的是，目前许多抗HER2药物已用于临床治疗以提高患者生存率。然而，一些HER2+患者（约15%）在接受曲妥珠单抗治疗后仍会产生耐药性，导致治疗失败。通过CCLE和METABRIC数据库分析，我们发现成纤维细胞生长因子受体4（FGFR4）mRNA在HER2+乳腺癌患者的肿瘤中检测到的水平较高（p < 0.001），并且与乳腺癌患者较差的生存率相关。通过回顾性免疫组织化学染色分析，我们检测到与对治疗有反应的乳腺癌患者相比，从对曲妥珠单抗治疗耐药的患者收集的乳腺癌组织中FGFR4蛋白的表达更高。一种FGFR4抑制剂（FGF401）可有效抑制曲妥珠单抗不敏感的患者来源异种移植（PDX）荷瘤小鼠的肿瘤生长。对于分子机制研究，我们证明在这些曲妥珠单抗不敏感的PDX肿瘤组织的肿瘤细胞膜上检测到了HER2/FGFR4蛋白复合物。在这些耐药乳腺癌细胞中进行曲妥珠单抗治疗后，FGFR4易位并进入细胞核。然而，FGF401治疗可阻断曲妥珠单抗诱导的耐药癌细胞中FGFR4/HER2细胞内结构域蛋白复合物的核转位。我们认为FGFR4的过表达以及与HER2形成复合物可作为分子标志物，以协助临床医生识别曲妥珠单抗耐药肿瘤。我们的结果表明，FGF401联合曲妥珠单抗作为曲妥珠单抗耐药乳腺癌患者的辅助治疗可能是一种潜在的新治疗策略。
