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Characterization of Nectin-4 expression in molecular subtypes of urothelial cancer and mechanisms of resistance to enfortumab vedotin

Funder: Bladder Cancer Advocacy Network

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Introduction:Nectin-4 (PVRL4) is a membrane protein overexpressed in urothelial cancer (UC). Nectin-4 is the drug target of Enfortumab Vedotin (EV), FDA-approved for metastatic UC. EV is an antibody-drug conjugate delivering MMAE to tumor cells expressing Nectin-4. Our objective was to determine molecular heterogeneity of tumors expressing Nectin-4, correlate Nectin-4 expression with clinical outcomes, and identify possible resistance mechanisms. Materials and Methods:We analyzed Nectin-4 expression in publicly available transcriptomic datasets of primary bladder tumors via the Affymetrix Human Exon 1.0 ST microarray (Seiler 2012, Seiler 2017, TCGA, Sjodahl 2017). The consensus molecular subtype classifier was applied (Kamoun 2019). Associations between Nectin-4 expression and clinical outcomes were analyzed. Nectin-4 expression was then examined across all available bladder cancer cell lines. Nectin-4 overexpressing and knockdown cell lines were generaged. We determined the dose-response curve of these cell lines to EV.Results:In primary bladder specimens, Nectin-4 expression is higher in luminal subtypes (LumP, LumNS, LumU) than basal (p<0.001), NE-like (p<0.001), and stroma-rich (p<0.001) subtypes. Compared with the lowest quartile of Nectin-4 expression, patients with higher Nectin-4 expression had better overall survival that trended towards significance (HR 0.48 95% CI 0.21-1.1, logrank p=0.07). In cell culture, HT-1376 (luminal) cells demonstrated higher levels of Nectin-4 expression than UMUC3 (basal) cells. Overexpression of Nectin-4 in UMUC3 cells demonstrated markedly increased sensitivity to EV. In contrast, knockdown of Nectin-4 expression in HT-1376 cells increased resistance to EV.Conclusion:Nectin-4 expression is associated with luminal subtypes of bladder cancer and may predict better clinical outcomes. Increased Nectin-4 expression enhances sensitivity to EV in vitro. Patients with luminal subtypes may benefit most from EV.
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    1112 Oncology and Carcinogenesis

  • RCDC


  • RCDC

    Clinical Research

  • RCDC

    Urologic Diseases




    2.1 Biological and endogenous factors

  • Health Research Areas


  • Broad Research Areas

    Basic Science