Nordic Nanovector ASA, Oslo, Norway.
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
PLoS One. 2022 Apr 29;17(4):e0267543. doi: 10.1371/journal.pone.0267543. eCollection 2022.
PARP inhibitors have been shown to increase the efficacy of radiotherapy in preclinical models. Radioimmunotherapy results in selective radiation cytotoxicity of targeted tumour cells. Here we investigate the combined effect of anti-CD37 β-emitting 177Lu-NNV003 radioimmunotherapy and the PARP inhibitor olaparib, and gene expression profiles in CD37 positive non-Hodgkin's lymphoma cell lines.
The combined effect of 177Lu-NNV003 and olaparib was studied in seven cell lines using a fixed-ratio ray design, and combination index was calculated for each combination concentration. mRNA was extracted before and after treatment with the drug combination. After RNA-sequencing, hierarchical clustering was performed on basal gene expression profiles and on differentially expressed genes after combination treatment from baseline. Functional gene annotation analysis of significant differentially expressed genes after combination treatment was performed to identify enriched biological processes.
The combination of olaparib and 177Lu-NNV003 was synergistic in four of seven cell lines, antagonistic in one and both synergistic and antagonistic (conditionally synergistic) in two, depending on the concentration ratio between olaparib and 177Lu-NNV003. Cells treated with the combination significantly overexpressed genes in the TP53 signalling pathway. However, cluster analysis did not identify gene clusters that correlate with the sensitivity of cells to single agent or combination treatment.
The cytotoxic effect of the combination of the PARP inhibitor olaparib and the β-emitting radioimmunoconjugate 177Lu-NNV003 was synergistic in the majority of tested lymphoma cell lines.
PARP 抑制剂已被证明可提高临床前模型中放射治疗的疗效。放射免疫疗法可导致靶向肿瘤细胞的选择性放射细胞毒性。在此，我们研究了抗 CD37β发射 177Lu-NNV003 放射免疫疗法和 PARP 抑制剂奥拉帕利联合应用，以及 CD37 阳性非霍奇金淋巴瘤细胞系中的基因表达谱。
采用固定比例射线设计研究了 177Lu-NNV003 和奥拉帕利在七种细胞系中的联合作用，并计算了每种联合浓度的组合指数。用药物组合处理前后提取 mRNA。进行 RNA-seq 后，对基础基因表达谱和组合治疗后与基线相比差异表达的基因进行层次聚类分析。对组合治疗后差异表达的显著基因进行功能基因注释分析，以确定富集的生物学过程。
在七种细胞系中的四种中，奥拉帕利和 177Lu-NNV003 的组合具有协同作用，在一种中具有拮抗作用，在两种中具有协同和拮抗作用（条件性协同作用），这取决于奥拉帕利和 177Lu-NNV003 之间的浓度比。用联合药物处理的细胞显著过表达 TP53 信号通路中的基因。然而，聚类分析并未确定与细胞对单药或联合治疗敏感性相关的基因簇。
PARP 抑制剂奥拉帕利和β发射放射免疫偶联物 177Lu-NNV003 的组合在大多数测试的淋巴瘤细胞系中具有协同的细胞毒性作用。
