TROP-2在乳头状肾细胞癌中的过表达支持了其作为抗体药物偶联物治疗靶点的潜力。

TROP-2 overexpression in papillary renal cell carcinoma supports its potential as a therapeutic target for antibody-drug-conjugate therapy.

作者信息

Kessler Carolina, von Brandenstein Melanie, Klümper Niklas, Krausewitz Philipp, Storz Enno, Rieger Constantin, Sperber Laurenz, Paffenholz Pia, Tolkach Yuri, Wirtz Ralph, Eckstein Markus, Heidenreich Axel, Weiten Richard

机构信息

Department of Urology, Uro-Oncology, Robot-Assisted and Specialized Urologic Surgery, University Hospital Cologne, Kerpener Str. 62, 50937 , Cologne, Germany.

Department of Urology, University Hospital Bonn, Bonn, Germany.

出版信息

World J Urol. 2025 Sep 1;43(1):522. doi: 10.1007/s00345-025-05880-2.

DOI:10.1007/s00345-025-05880-2

PMID:40888912

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12401752/

Abstract

OBJECTIVE

To evaluate the expression of trophoblast cell surface antigen-2 (TROP-2), a broadly expressed antibody-drug conjugate (ADC) target, in non-clear cell renal cell carcinoma (nccRCC), and to perform a proof-of-concept analysis assessing the cytotoxic efficacy of the TROP-2-directed ADC Sacituzumab govitecan (SG) in RCC cell lines.

METHODS

A cohort comprising clear cell RCC (ccRCC, = 44), papillary (pRCC, = 22), chromophobe (chRCC, = 22), and benign renal tumors ( = 8, including oncocytoma and angiomyolipoma) was analysed using reverse transcription quantitative PCR (RT-qPCR), immunohistochemistry (IHC) with H-score quantification, and enzyme-linked immunosorbent assay (ELISA). In RCC cell lines, TROP-2 protein levels were assessed by Western blotting and flow cytometry, and SG cytotoxicity was evaluated using MTT assays.

RESULTS

TROP-2 mRNA levels were significantly elevated in pRCC compared to ccRCC, chRCC and benign renal tumors ( < 0.001). IHC revealed moderate to strong membranous TROP-2 expression in most pRCC cases [ = 20/22 with H-score ≥ 100, median H-score 265 (IQR 202.5–290)], while TROP-2 expression was absent or weak in ccRCC and chRCC ( < 0.0001). Soluble TROP-2 was detectable in patient serum of RCC patients and strongly correlated with tissue expression (ρ = 0.78, = 0.0001, R = 0.52). In vitro, TROP-2-positive Caki-1 cells exhibited significant growth inhibition after SG treatment, whereas TROP-2-negative 769-P cells showed resistance ( < 0.01).

CONCLUSION

The selective overexpression of TROP-2 in pRCC, and its functional relevance demonstrated in vitro, provide compelling preclinical evidence supporting TROP-2 as a therapeutic target. These findings support further investigation of TROP-2-directed ADCs, such as SG, in patients with metastatic TROP-2-positive pRCC.

SUPPLEMENTARY INFORMATION

The online version contains supplementary material available at 10.1007/s00345-025-05880-2.

摘要

目的

评估滋养层细胞表面抗原2（TROP-2）（一种广泛表达的抗体药物偶联物（ADC）靶点）在非透明细胞肾细胞癌（nccRCC）中的表达，并进行概念验证分析，评估靶向TROP-2的ADC药物戈沙妥珠单抗（SG）在肾癌细胞系中的细胞毒性疗效。

方法

采用逆转录定量PCR（RT-qPCR）、免疫组化（IHC）及H评分定量法和酶联免疫吸附测定（ELISA），对一个包含透明细胞肾细胞癌（ccRCC，n = 44）、乳头状肾细胞癌（pRCC，n = 22）、嫌色细胞肾细胞癌（chRCC，n = 22）和良性肾肿瘤（n = 8，包括嗜酸细胞瘤和血管平滑肌脂肪瘤）的队列进行分析。在肾癌细胞系中，通过蛋白质印迹法和流式细胞术评估TROP-2蛋白水平，并使用MTT法评估SG的细胞毒性。

结果

与ccRCC、chRCC和良性肾肿瘤相比，pRCC中TROP-2 mRNA水平显著升高（P < 0.001）。免疫组化显示，大多数pRCC病例中TROP-2呈中度至强膜性表达[20/22例H评分≥100，H评分中位数为265（四分位间距202.5 - 290）]，而ccRCC和chRCC中TROP-2表达缺失或较弱（P < 0.0001）。在RCC患者的血清中可检测到可溶性TROP-2，且与组织表达密切相关（ρ = 0.78，P = 0.0001，R = 0.52）。在体外，SG处理后，TROP-2阳性的Caki-1细胞生长受到显著抑制，而TROP-2阴性的769-P细胞则表现出耐药性（P < 0.01）。