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

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, n = 44), papillary (pRCC, n = 22), chromophobe (chRCC, n = 22), and benign renal tumors (n = 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 (p < 0.001). IHC revealed moderate to strong membranous TROP-2 expression in most pRCC cases [n = 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 (p < 0.0001). Soluble TROP-2 was detectable in patient serum of RCC patients and strongly correlated with tissue expression (ρ = 0.78, p = 0.0001, R(2) = 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 (p < 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.