PO.TB04.06 · 肿瘤生物学
在前列腺癌PDX中建立奥拉帕利耐药模型以阐明PARP抑制剂逃逸机制
Modeling olaparib resistance in prostate cancer PDXs to elucidate PARP inhibitor escape mechanisms
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
患者来源异种移植瘤（PDX）是模拟前列腺癌（PCa）生物学特性和评估治疗反应的重要临床前工具。过去数年，我们建立并全面表征了一组包含15个前列腺癌PDX模型的模型库，这些模型重现了人类疾病的组织学和分子异质性。虽然奥拉帕利（olaparib）等PARP抑制剂为携带BRCA1/2突变或同源重组缺陷（HRD）的患者带来临床获益，但耐药性不可避免地出现，并仍是一项重大临床挑战。在此，我们展示了利用我们的PCa PDX模型库为表征PARP抑制剂耐药机制及识别规避PARPi逃逸策略铺平道路的研究见解。在整个生物样本库中评估了对奥拉帕利的治疗反应，同时评估了同源重组修复（HRR）状态。大多数PDX模型表现出内在耐药性，而三个模型表现出显著敏感性。值得注意的是，一个携带DNA损伤修复改变的神经内分泌前列腺癌（NEPC）PDX表现出明显的奥拉帕利敏感性，为PARP抑制剂在神经内分泌背景下的活性提供了首个临床前证据。随后将这三个敏感模型进行慢性治疗直至肿瘤复发，从而产生获得性奥拉帕利耐药衍生模型。通过组织病理学分析以及转录组和基因组分析，将耐药PDX与其同基因敏感对应模型进行比较，重点关注DNA修复和代偿性通路。多组学分析提示涉及同源重组的部分恢复和替代性DNA修复通路激活等机制。总体而言，这一独特的PCa PDX模型库连同新生成的奥拉帕利耐药衍生模型，构成了解析PARP抑制剂耐药机制以及为前列腺癌下一代治疗组合开发提供依据的宝贵临床前资源。
查看英文原文 English abstract
Patient-derived xenografts (PDXs) are essential preclinical tools for modeling prostate cancer (PCa) biology and assessing therapeutic responses. Over the past years, we have established and comprehensively characterized a panel of 15 prostate cancer PDX models that recapitulate the histological and molecular heterogeneity of human disease. While PARP inhibitors such as olaparib provide clinical benefit to patients harboring BRCA1/2 mutations or homologous recombination deficiency (HRD), resistance inevitably emerges and remains a major clinical challenge. Here, we present insights that pave the way for characterizing mechanisms of PARP inhibitor resistance and identifying strategies to circumvent PARPi escape using our panel of PCa PDX models. Therapeutic responses to olaparib were evaluated across the biobank, alongside assessment of homologous recombination repair (HRR) status. Most PDX models displayed intrinsic resistance, whereas three showed marked sensitivity. Notably, a neuroendocrine prostate cancer (NEPC) PDX harboring DNA damage-repair alterations exhibited pronounced olaparib sensitivity, providing the first preclinical evidence supporting PARP inhibitor activity in a neuroendocrine context. These three sensitive models were then exposed to chronic treatment until tumor recurrence, generating acquired olaparib-resistant derivatives. Resistant PDXs were compared with their isogenic sensitive counterparts through histopathological analysis and transcriptomic and genomic profiling, with a focus on DNA repair and compensatory pathways. Multi-omic analyses indicate involvement of mechanisms such as partial restoration of homologous recombination and activation of alternative DNA repair pathways. Overall, this unique PCa PDX panel, together with the newly generated olaparib-resistant derivatives, constitutes a valuable preclinical resource for deciphering PARP inhibitor resistance mechanisms and informing the development of next-generation therapeutic combinations for prostate cancer.
利益披露 Disclosure
N. Bidan, None..
C. Beraud, None..
E. Indersie, None..
M. Tavernier, None..
C. Krucker, None..
E. Potiron, None..
P. Lluel, None..
O. Déas, None.