Purpose: Enfortumab vedotin (EV) is an antibody–drug conjugate (ADC) targeting NECTIN4 (encoded by the PVRL4/NECTIN4 gene) approved for treatment-refractory metastatic urothelial cancer. Factors that mediate sensitivity or resistance to EV are unknown. In this study, we sought to (i) examine heterogeneity of NECTIN4 gene expression across molecular subtypes of bladder cancer and (ii) determine whether NECTIN4 expression mediates EV sensitivity or resistance. Experimental Design: Molecular subtyping and NECTIN4 expression data from seven muscle-invasive bladder cancer clinical cohorts ( n = 1,915 total specimens) were used to assess NECTIN4 expression across molecular subtypes. The outcome of the transcriptomic analysis was relative NECTIN4 expression in the consensus molecular subtypes of bladder cancer. Expression of NECTIN4 was validated in bladder cancer cell lines. NECTIN4 was stably overexpressed or knocked down in basal and luminal bladder cancer cell lines and EV drug sensitivity assays were performed, as measured by cell proliferation and clonogenic assays. Results: NECTIN4 expression is heterogenous across molecular subtypes of bladder cancer and significantly enriched in luminal subtypes. NECTIN4 expression is positively correlated with luminal markers GATA3, FOXA1 , and PPARG across all cohorts. NECTIN4 expression is both necessary and sufficient for EV sensitivity in luminal and basal subtypes of urothelial bladder cancer cells. Downregulation of NECTIN4 leads to EV resistance. Conclusions: Sensitivity to EV is mediated by expression of NECTIN4 , which is enriched in luminal subtypes of bladder cancer. These findings may have implications for biomarker development, patient selection, and the inclusion of molecular subtyping in ongoing and future EV clinical trials. See related commentary by Teo and Rosenberg, [p. 4950][1] [1]: /lookup/volpage/27/4950?iss=18

中文翻译：

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尿路上皮癌分子亚型中 NECTIN4 表达的异质性介导对 Enfortumab Vedotin 的敏感性


目的：Enfortumab vedotin (EV) 是一种靶向 NECTIN4（由 PVRL4/NECTIN4 基因编码）的抗体药物偶联物 (ADC)，被批准用于治疗难治性转移性尿路上皮癌。介导 EV 敏感性或耐药性的因素尚不清楚。在这项研究中，我们试图（i）检查膀胱癌分子亚型中 NECTIN4 基因表达的异质性，以及（ii）确定 NECTIN4 表达是否介导 EV 敏感性或耐药性。实验设计：使用来自 7 个肌层浸润性膀胱癌临床队列（总共 n = 1,915 个样本）的分子亚型和 NECTIN4 表达数据来评估跨分子亚型的 NECTIN4 表达。转录组分析的结果是膀胱癌共有分子亚型中 NECTIN4 的相对表达。 NECTIN4 的表达在膀胱癌细胞系中得到验证。 NECTIN4 在基底和管腔膀胱癌细胞系中稳定过表达或敲低，并进行了 EV 药物敏感性测定，通过细胞增殖和克隆形成测定进行测量。结果：NECTIN4 表达在膀胱癌分子亚型之间存在异质性，并且在管腔亚型中显着富集。在所有队列中，NECTIN4 表达与管腔标记物 GATA3、FOXA1 和 PPARG 呈正相关。 NECTIN4 表达对于膀胱尿路上皮癌细胞的管腔亚型和基底亚型的 EV 敏感性来说既是必要的也是充分的。 NECTIN4 的下调会导致 EV 耐药。结论：对 EV 的敏感性是由 NECTIN4 的表达介导的，NECTIN4 在膀胱癌的管腔亚型中丰富。 这些发现可能对生物标志物开发、患者选择以及将分子亚型纳入正在进行和未来的 EV 临床试验产生影响。参见 Teo 和 Rosenberg 的相关评论，[p. 11]。 4950][1][1]：/lookup/volpage/27/4950？国际空间站=18