针对患者来源的胰腺癌细胞中增强子起始途径的启动治疗。

Priming therapy by targeting enhancer-initiated pathways in patient-derived pancreatic cancer cells.

机构信息

Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France; Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Facultad de Medicina, Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Medicina, Departamento de Microbiología, Parasitología e Inmunología, Buenos Aires, Argentina.

Tumour Identity Card Program (CIT), French League Against Cancer, Paris, France.

出版信息

EBioMedicine. 2023 Jun;92:104602. doi: 10.1016/j.ebiom.2023.104602. Epub 2023 May 4.

DOI:10.1016/j.ebiom.2023.104602

PMID:37148583

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10189188/

Abstract

BACKGROUND

Systems biology leveraging multi-OMICs technologies, is rapidly advancing development of precision therapies and matching patients to targeted therapies, leading to improved responses. A new pillar of precision oncology lies in the power of chemogenomics to discover drugs that sensitizes malignant cells to other therapies. Here, we test a chemogenomic approach using epigenomic inhibitors (epidrugs) to reset patterns of gene expression driving the malignant behavior of pancreatic tumors.

METHODS

We tested a targeted library of ten epidrugs targeting regulators of enhancers and super-enhancers on reprogramming gene expression networks in seventeen patient-derived primary pancreatic cancer cell cultures (PDPCCs), of both basal and classical subtypes. We subsequently evaluated the ability of these epidrugs to sensitize pancreatic cancer cells to five chemotherapeutic drugs that are clinically used for this malignancy.

FINDINGS

To comprehend the impact of epidrug priming at the molecular level, we evaluated the effect of each epidrugs at the transcriptomic level of PDPCCs. The activating epidrugs showed a higher number of upregulated genes than the repressive epidrugs (χ test p-value <0.01). Furthermore, we developed a classifier using the baseline transcriptome of epidrug-primed-chemosensitized PDPCCs to predict the best epidrug-priming regime to a given chemotherapy. Six signatures with a significant association with the chemosensitization centroid (R ≤ -0.80; p-value < 0.01) were identified and validated in a subset of PDPCCs.

INTERPRETATION

We conclude that targeting enhancer-initiated pathways in patient-derived primary cells, represents a promising approach for developing new therapies for human pancreatic cancer.

FUNDING

This work was supported by INCa (Grants number 2018-078 to ND and 2018- 079 to JI), Canceropole PACA (ND), Amidex Foundation (ND), and INSERM (JI).

摘要

背景

系统生物学利用多组学技术，正在迅速推进精准治疗的发展，并将患者与靶向治疗相匹配，从而提高治疗效果。精准肿瘤学的一个新支柱在于化学生物组学的力量，它可以发现使恶性细胞对其他治疗敏感的药物。在这里，我们使用表观基因组抑制剂（epidrugs）测试了一种化学生物组学方法，以重置驱动胰腺肿瘤恶性行为的基因表达模式。

方法

我们在十七种源自患者的原发性胰腺癌细胞培养物（PDPCC）中，针对增强子和超级增强子调节剂的靶向文库测试了十种靶向表观基因组抑制剂，这些 PDPCC 既有基底型又有经典型。随后，我们评估了这些 epidrugs 使胰腺癌细胞对五种临床上用于治疗这种恶性肿瘤的化疗药物敏感的能力。

发现

为了从分子水平上理解 epidrug 引发的影响，我们评估了每种 epidrugs 在 PDPCC 的转录组水平上的影响。激活 epidrugs 比抑制性 epidrugs 显示出更高数量的上调基因（χ检验 p 值<0.01）。此外，我们使用经 epidrug 引发的化疗敏感的 PDPCC 的基线转录组开发了一个分类器，以预测给定化疗的最佳 epidrug 引发方案。在 PDPCC 的一个亚集中，确定并验证了六个与化疗敏感中心体具有显著关联的特征（R≤-0.80；p 值<0.01）。