Heterogeneity in NECTIN4 Expression Across Molecular Subtypes of Urothelial Cancer Mediates Sensitivity to Enfortumab Vedotin

• Published in: Clinical cancer research Vol. 27; no. 18; pp. 5123 - 5130
• Main Authors: Chu, Carissa E, Sjöström, Martin, Egusa, Emily A, Gibb, Ewan A, Badura, Michelle L, Zhu, Jun, Koshkin, Vadim S, Stohr, Bradley A, Meng, Maxwell V, Pruthi, Raj S, Friedlander, Terence W, Lotan, Yair, Black, Peter C, Porten, Sima P, Feng, Felix Y, Chou, Jonathan
• Format: Journal Article
• Language: English
• Published: United States 15-09-2021
• Subjects: Antibodies, Monoclonal - therapeutic use; Carcinoma, Transitional Cell - classification; Carcinoma, Transitional Cell - drug therapy; Carcinoma, Transitional Cell - genetics; Cell Adhesion Molecules - genetics; Female; Gene Expression Regulation, Neoplastic; Humans; Immunoconjugates - therapeutic use; Tumor Cells, Cultured; Urinary Bladder Neoplasms - classification; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - genetics
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-20-4175

Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) targeting NECTIN4 (encoded by the
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
gene expression across molecular subtypes of bladder cancer and (ii) determine whether NECTIN4 expression mediates EV sensitivity or resistance.
Molecular subtyping and
expression data from seven muscle-invasive bladder cancer clinical cohorts (
= 1,915 total specimens) were used to assess
expression across molecular subtypes. The outcome of the transcriptomic analysis was relative
expression in the consensus molecular subtypes of bladder cancer. Expression of
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.
expression is heterogenous across molecular subtypes of bladder cancer and significantly enriched in luminal subtypes.
expression is positively correlated with luminal markers
, and
across all cohorts.
expression is both necessary and sufficient for EV sensitivity in luminal and basal subtypes of urothelial bladder cancer cells. Downregulation of
leads to EV resistance.
Sensitivity to EV is mediated by expression of
, 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.
.