通过外体药物测试患者源性乳头状肾癌细胞揭示EGFR和BCL2家族是治疗的靶点。
Ex Vivo Drug Testing in Patient-derived Papillary Renal Cancer Cells Reveals EGFR and the BCL2 Family as Therapeutic Targets.
发表日期：2023 Mar 16
作者：
Silvia Angori, Amir Banaei-Esfahani, Katharina Mühlbauer, Hella A Bolck, Abdullah Kahraman, Tülay Karakulak, Cédric Poyet, Michaela Feodoroff, Swapnil Potdar, Olli Kallioniemi, Vilja Pietiäinen, Peter Schraml, Holger Moch
来源：
European Urology Focus
摘要：
免疫检查点抑制剂和抗血管生成药物被用于高级乳头状肾细胞癌（pRCC）的一线治疗，但这些治疗对pRCC的响应率较低。为了生成和表征一个功能性的离体模型，以识别先进的pRCC的新的治疗选择。我们从七个病人的pRCC样本建立了患者源性细胞培养物（PDCs），并通过基因组分析和药物筛查对它们进行了表征。通过拷贝数分析和全外显子测序的综合分子表征，确立pRCC PDCs与原始肿瘤的一致性。我们通过为每个PDC生成药物得分来评估它们对新药的敏感性。PDCs证实pRCC的特异性拷贝数变异，如染色体7、16和17的增益。全外显子测序揭示PDCs保留了pRCC特异性驱动基因的突变。我们进行了526种新型和肿瘤相关化合物的药物筛查。虽然接触传统药物显示出低效，但结果突出了EGFR和BCL2族成员的抑制剂在pRCC PDCs中是最有效的靶点。在新建立的pRCC PDCs上进行高通量药物测试揭示了EGFR和BCL2家族成员的抑制可能是pRCC的治疗策略。我们采用了一种新的方法，从一种特定的肾癌中生成患者源性细胞。我们展示了这些细胞与原始肿瘤具有相同的基因背景，并可用作研究此种肾癌新治疗选项的模型。版权所有©2023作者。由Elsevier B.V.出版。保留所有权利。
Immune checkpoint inhibitors and antiangiogenic agents are used for first-line treatment of advanced papillary renal cell carcinoma (pRCC) but pRCC response rates to these therapies are low.To generate and characterise a functional ex vivo model to identify novel treatment options in advanced pRCC.We established patient-derived cell cultures (PDCs) from seven pRCC samples from patients and characterised them via genomic analysis and drug profiling.Comprehensive molecular characterisation in terms of copy number analysis and whole-exome sequencing confirmed the concordance of pRCC PDCs with the original tumours. We evaluated their sensitivity to novel drugs by generating drug scores for each PDC.PDCs confirmed pRCC-specific copy number variations such as gains in chromosomes 7, 16, and 17. Whole-exome sequencing revealed that PDCs retained mutations in pRCC-specific driver genes. We performed drug screening with 526 novel and oncological compounds. Whereas exposure to conventional drugs showed low efficacy, the results highlighted EGFR and BCL2 family inhibition as the most effective targets in our pRCC PDCs.High-throughput drug testing on newly established pRCC PDCs revealed that inhibition of EGFR and BCL2 family members could be a therapeutic strategy in pRCC.We used a new approach to generate patient-derived cells from a specific type of kidney cancer. We showed that these cells have the same genetic background as the original tumour and can be used as models to study novel treatment options for this type of kidney cancer.Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.