乳房外佩吉特病（EMPD）是一种罕见的皮肤上皮内腺癌，通常采用广泛的局部切除治疗。不幸的是，许多转移患者对化疗反应不佳。虽然一些研究探讨了曲妥珠单抗对人表皮生长因子受体 2 (HER2) 阳性 EMPD 的有效性，但抗 HER2 治疗后可能会出现曲妥珠单抗耐药性 (TR)。在这项研究中，我们建立了 TR EMPD 患者来源的异种移植物 (PDX)，复制了初始 EMPD 肿瘤的组织学和 HER2 表达特征。癌症基因分析显示 TR 肿瘤中 PTEN 基因缺失，通过免疫组织化学染色和免疫印迹测试蛋白质表达水平进一步证实了这一点。 PTEN 水平降低与蛋白激酶 B (Akt) 磷酸化增加和 p27 下调相关，这表明 EMPD 细胞中曲妥珠单抗耐药的潜在机制。在曲妥珠单抗敏感的 EMPD-PDX 小鼠模型中，PTEN 抑制剂部分恢复了曲妥珠单抗介导的肿瘤消退。 TR EMPD-PDX 对靶向治疗（拉帕替尼、abemaciclib、palbociclib）和化疗（艾日布林、多西他赛、曲妥珠单抗 deruxtecan）反应良好。本研究展示了一种创新的 TR EMPD-PDX 模型，并介绍了针对 TR EMPD 肿瘤的各种治疗方法的有希望的抗肿瘤效果.© 2024。作者获得 Springer Nature Limited 的独家许可。

Extramammary Paget disease (EMPD) is a rare, cutaneous intraepithelial adenocarcinoma typically treated with wide local excision. Unfortunately, a number of patients with metastases show poor responses to chemotherapy. While some studies have explored trastuzumab's effectiveness against EMPD positive for human epidermal growth factor receptor 2 (HER2), trastuzumab resistance (TR) may emerge after anti-HER2 therapy.In this study, we established TR EMPD patient-derived xenografts (PDX) that replicated the histological and HER2 expression traits of naive EMPD tumours.Cancer gene analyses revealed a loss of the PTEN gene in TR tumours, which was further confirmed by immunohistochemical staining and immunoblotting to test for protein expression levels. Reduced PTEN levels correlated with increased protein kinase B (Akt) phosphorylation and p27 downregulation, suggesting a potential mechanism for trastuzumab resistance in EMPD cells. In the trastuzumab-sensitive EMPD-PDX mouse model, PTEN inhibitors partially restored trastuzumab-mediated tumour regression. The TR EMPD-PDX responded favourably to targeted therapy (lapatinib, abemaciclib, palbociclib) and chemotherapy (eribulin, docetaxel, trastuzumab deruxtecan).This study demonstrates an innovative TR EMPD-PDX model and introduces promising antineoplastic effects with various treatments for TR EMPD tumours.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.