PO.ET03.06 · 实验与分子治疗
新型体内JIMT-1 DS8201a耐药模型的构建与表征及其疗效评估
Development and characterization of a novel in vivo JIMT-1 DS8201a resistant model and its efficacy evaluation
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
Trastuzumab deruxtecan，商品名Enhertu（DS-8201a），是一种新一代HER-2靶向抗体-药物偶联物（ADC），可释放拓扑异构酶抑制剂有效载荷。由于Deruxtecan具有膜通透性，它表现出强烈的旁观者效应，因为它可扩散进入邻近细胞，杀伤抗原阴性细胞。尽管取得了临床成功并重新激发了对ADC的兴趣，但由肿瘤异质性和基因组改变驱动的获得性和原发性耐药仍是一项重大考量。为研究肿瘤耐药机制，我们内部建立了DS8201a耐药的JIMT-1细胞系及相应的体内肿瘤模型。我们还获取了一个原发性耐药的胃癌PDX模型（GAX227M），并从该PDX衍生出一个类器官模型（PDXO）。基于体外和体内筛选，我们证明所有模型对DS8201a均有显著耐药。此外，我们对JIMT-1 DS8201a耐药模型进行了全面的全外显子组测序（WES）和RNA测序（RNA-seq），目前正在进行生物信息学分析。我们的临床前工具箱旨在帮助解析耐药机制并指导克服ADC耐药的合理策略。这些见解将为新一代ADC的开发提供参考，并改善HER-2阳性异质性肿瘤的治疗结局。
查看英文原文 English abstract
Trastuzumab deruxtecan, marketed as Enhertu (DS-8201a) is a next generation HER-2 targeted Antibody-Drug Conjugate (ADC), that releases a topoisomerase inhibitor payload. As the Deruxtecan is membrane permeable it exhibits a strong bystander effect as it can diffuse into neighboring cells, killing antigen negative cells. Despite clinical success and reinvigorating ADC interest, acquired and primary resistance driven by tumor heterogeneity and genomic alterations remain a major consideration. To investigate tumor resistance mechanisms, we have established in house a DS8201a resistant JIMT-1 cell line and the corresponding in vivo tumor model. We have also acquired a primary resistant gastric cancer PDX model (GAX227M), and we have derived an organoid model (PDXO) from this PDX. Based on in vitro and in vivo screening, we have demonstrated significant resistance to DS8201a in all models. Furthermore, we have comprehensive whole-exome sequencing (WES) and RNA sequencing (RNA-seq) for the JIMT-1 DS8201a-resistant model that is currently undergoing bioinformatic analysis. Our preclinical toolbox is designed to help decipher resistance mechanisms and guide rational strategies to overcome ADC resistance. These insights will inform the development of next-generation ADC's and improve outcomes in HER-2 positive heterogenous tumors.
利益披露 Disclosure
Q. Chen, None..
L. Zhang, None..
Y. Xu, None..
J. Zhang, None..
L. Li, None..
G. Liang, None..
M. Shao, None..
F. Feng, None..
Y. Yin, None.