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. 2025 Jun 25;95(1):62.
doi: 10.1007/s00280-025-04783-8.

Clinical relevance of Nectin-4 downregulation and biological changes caused by cytotoxic chemotherapy in bladder cancer

Makito Miyake  1 , Takuya Owari  2   3 , Kota Iida  2 , Sayuri Onishi  2 , Nobutaka Nishimura  2 , Tomomi Fujii  4 , Cynthia N Jinno  5 , Hideki Furuya  5 , Yuki Oda  2 , Tatsuki Miyamoto  2 , Mitsuru Tomizawa  2 , Takuto Shimizu  2 , Kenta Onishi  2 , Shunta Hori  2 , Yosuke Morizawa  2 , Daisuke Goto  2 , Yasushi Nakai  2 , Nobumichi Tanaka  2   6 , Noriyoshi Miura  7 , Tadahiko Kikugawa  7 , Takashi Saika  7 , Charles Rosser  8 , Kiyohide Fujimoto  2
Affiliations

Clinical relevance of Nectin-4 downregulation and biological changes caused by cytotoxic chemotherapy in bladder cancer

Makito Miyake et al. Cancer Chemother Pharmacol. .

Abstract

Introduction: Mechanism underlying resistance to enfortumab vedotin (EV) and prognostication of Nectin-4 expression in muscle-invasive bladder cancer (MIBC) remains unclear.

Methods: We generated gemcitabine-resistant HT-1376 and cisplatin-resistant HT-1376 cells generated from parental HT1376 cells (derived from MIBC). Transcriptome analysis was conducted to explore the biological function of differentially expressed genes detected in chemoresistant HT-1376 cells compared to parental HT-1376. In 70 patients with MIBC undergoing radical cystectomy, unsupervised hierarchical clustering was performed using immunohistochemical staining pattern with GATA3, KRT20, KRT5/6, KRT14, and Nectin-4 expression derived from the gene expression-based Nectin-4-modified NanoString molecular classification: Luminal-Nec4-High, Luminal-Nec4-Low, Basal-Nec4-High, and Basal-Nec4-Low subgroups.

Results: We found significant downregulation of Nectin-4 expression along with epithelial-to-mesenchymal transition in chemoresistant HT-1376 cells. Exogenous expression of NECTIN4 in chemoresistant HT-1376 cells partially restored sensitivity to EV. RNA seq identified differentially expressed genes, including Nectin-4 and small proline-rich proteins, downregulated in chemoresistant HT-1376 cells. Over-representation analysis using GO and KEGG revealed upregulation of gene sets enriched for ribosome biogenesis-related pathways in chemoresistant HT-1376 cells. Nectin-4-modified molecular subtype resulted in better stratification of survival-the Luminal-Nec4-High subgroup had the best and the Basal-Nec4-Low subgroup had the worst prognosis. Comparing molecular subtypes of MIBC cells between transurethral resection specimens and matched radical cystectomy specimens revealed that 43% of neoadjuvant chemotherapy-treated patients with luminal subtype tumors showed a marked shift to the basal subtype in the cystectomy specimens.

Conclusion: The clinical utility of Nection-4, associated molecules, and Nectin-4-modified molecular subtype need to be studied for better management strategies for MIBC.

Keywords: Bladder neoplasm; Chemoresistance; Enfortumab Vedotin; Molecular classification; RNA seq.

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Conflict of interest statement

Declarations. Conflict of interest: Kiyohide Fujimoto received speaking/lecture fees and Makito Miyake received speaking/lecture and consultation/advisory fees from Astellas Pharma Inc. Other authors disclose no potential conflicts of interest. Ethics statement: Approval of the research protocol by an Institutional Reviewer Board: ID: 1256/2891.

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