PO.TB04.06 · 肿瘤生物学
对Enhertu®获得性耐药的三阴性乳腺癌PDX模型：揭示逃逸机制的临床前平台
Triple-negative breast cancer PDX models with acquired resistance to Enhertu ® : A preclinical platform to uncover mechanisms of escape
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作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
三阴性乳腺癌（TNBC）仍是一种侵袭性强、异质性高、预后差的亚型。尽管抗体偶联药物Enhertu®（曲妥珠单抗deruxtecan，T-DXd）在一部分HER2低表达的TNBC中显示出临床活性，但耐药的快速出现限制了其长期疗效。因此，稳健的临床前模型对于研究耐药机制和评估新型治疗组合至关重要。在我们由40个TNBC患者来源异种移植（PDX）组成的模型组中，有14个在体内接受了Enhertu®暴露，其中11个敏感。在这些模型中，部分PDX模型被持续治疗直至产生获得性耐药。迄今为止，我们已通过持续T-DXd暴露从3个初始敏感模型建立了5个耐药衍生模型。通过RNA测序（HTSeq）进行转录组分析，随后进行基于DESeq的标准化和差异表达分析。功能富集分析聚焦于与内吞作用、受体循环、溶酶体运输、药物外排和DNA修复相关的预定义通路。差异表达分析揭示了数百个显著调控的基因。通过免疫组化评估HER2表达，并详细检测了溶酶体组织蛋白酶（CTSD、CTSB、CTSL）的RNA-Seq表达水平和突变状态，因为它们可能参与所观察到的耐药机制。此外，还用HER2靶向药物和拓扑异构酶I抑制剂对耐药模型进行了检测，以评估Enhertu®这两个药理学靶点在耐药机制中的各自贡献。总体而言，TNBC PDX模型对Enhertu®的耐药涉及多因素适应，包括信号通路重编程、药物外排改变和DNA修复的调节。这一耐药模型集合是研究耐药机制和支持新型治疗策略开发的宝贵临床前资源。
查看英文原文 English abstract
Triple-negative breast cancer (TNBC) remains an aggressive and heterogeneous subtype with a poor prognosis. Although the antibody-drug conjugate Enhertu® (trastuzumab deruxtecan, T-DXd) has shown clinical activity in a subset of TNBCs with low HER2 expression, the rapid emergence of resistance limits its long-term efficacy. Robust preclinical models are therefore essential to investigate resistance mechanisms and evaluate novel therapeutic combinations. Within our panel of 40 TNBC patient-derived xenografts (PDXs), 14 were exposed in vivo to Enhertu®, of which 11 were sensitive. Among these, some PDX models were treated until the development of acquired resistance. To date, we have established five resistant derivatives from three initially sensitive models through continuous T-DXd exposure. Transcriptomic profiling was performed by RNA sequencing (HTSeq), followed by DESeq-based normalization and differential expression analysis. Functional enrichment analyses focused on predefined pathways related to endocytosis, receptor recycling, lysosomal trafficking, drug efflux, and DNA repair. Differential expression analysis revealed hundreds of significantly modulated genes. HER2 expression was assessed by immunohistochemistry, and RNA-Seq expression levels and mutational status of lysosomal cathepsins (CTSD, CTSB, CTSL) were examined in detail, given their potential involvement in the observed resistance mechanisms. In addition, resistant models were tested with HER2-targeting agents and a topoisomerase I inhibitor to evaluate the respective contributions of the two pharmacological targets of Enhertu® in the resistance mechanisms. Overall, resistance to Enhertu® in TNBC PDX models involves multifactorial adaptations, including signaling pathway reprogramming, altered drug efflux, and modulation of DNA repair. This collection of resistant models represents a valuable preclinical resource to investigate resistance mechanisms and to support the development of novel therapeutic strategies.
利益披露 Disclosure
E. Indersie, None..
B. Guerrin, None..
E. Delhorbe, None..
E. Cyprien, None..
E. Darbinean, None..
D. Nicolle, None..
M. Tavernier, None..
O. Déas, None.