Pharmacogenetics and Pharmacogenomics Laboratory, School of Pharmacy, Chongqing Medical University, Chongqing, 400016, China.
Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Mol Med. 2024 Nov 11;30(1):209. doi: 10.1186/s10020-024-00934-4.
Patient-derived xenograft (PDX) is currently considered a preferred preclinical model to evaluate drug sensitivity, explore drug resistance mechanisms, and select individualized treatment regimens.
Histopathological examination, immunohistochemistry and whole-exome sequencing confirmed similarity between our PDX tumors and primary tumors in terms of morphology and genetic characteristics. The drug reactivity of the PDX tumor was validated in vivo. The mechanisms of acquired resistance to Osimertinib PDX tumors were investigated by WES and WB.
We successfully established 13 NSCLC-PDXs derived from 62 patients, including eight adenocarcinomas, four squamous-cell carcinoma, and one large-cell neuroendocrine carcinoma. Histological subtype and clinical stage were significant factors affecting the successful PDXs establishment. The treatment responses to conventional chemotherapy in PDXs were entirely consistent with that of their corresponding patients. According to the genetic status of tumors, more appropriate targeted agents were selected in PDXs for their corresponding patients as alternative treatment options. In addition, a PDX model with acquired resistance to osimertinib was induced, and the overactivation of RAS mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) signaling pathway caused by the dual-specificity phosphatase 6 (DUSP6) M62I mutation was found to play a key role in the development of osimertinib resistance. Trametinib, a specific inhibitor of the MAPK-ERK pathway significantly slowed down the tumor growth in osimertinib-resistant PDX models, providing an alternative treatment in patients after osimertinib failure.
患者来源的异种移植（PDX）目前被认为是评估药物敏感性、探索耐药机制和选择个体化治疗方案的首选临床前模型。
通过组织病理学检查、免疫组织化学和全外显子组测序，证实我们的 PDX 肿瘤在形态学和遗传特征方面与原发肿瘤具有相似性。体内验证了 PDX 肿瘤对药物的反应性。通过 WES 和 WB 研究了 PDX 肿瘤对奥希替尼获得性耐药的机制。
我们成功建立了 13 例来自 62 例患者的 NSCLC-PDX，包括 8 例腺癌、4 例鳞状细胞癌和 1 例大细胞神经内分泌癌。组织学亚型和临床分期是影响 PDX 成功建立的重要因素。PDX 对常规化疗的反应与相应患者的反应完全一致。根据肿瘤的遗传状态，为 PDX 患者选择了更合适的靶向药物作为替代治疗选择。此外，还诱导了对奥希替尼耐药的 PDX 模型，发现双特异性磷酸酶 6（DUSP6）M62I 突变导致 RAS 丝裂原活化蛋白激酶（MAPK）-细胞外信号调节激酶（ERK）信号通路的过度激活在奥希替尼耐药的发展中起关键作用。MAPK-ERK 通路的特异性抑制剂 trametinib 显著减缓了奥希替尼耐药 PDX 模型中的肿瘤生长，为奥希替尼治疗失败后的患者提供了一种替代治疗方法。
