Study of the mechanisms of resistance to the Antibody-drug conjugate Enfortumab Vedotin in urothelial carcinoma

Authors

• IT Stukes
• M-J Lee
• A Youseffi-Rad
• AB Apolo
• S Boudjadi

Abstract

Antibody-drug conjugates (ADCs) are a promising subset of targeted therapies in cancer biology that consist of a monoclonal antibody, a linker, and a chemotherapeutic payload. Enfortumab vedotin (EV) is an ADC that targets Nectin-4, a transmembrane protein highly expressed in urothelial carcinoma (UC). EV was recently approved by the FDA for the treatment of adult patients with locally advanced or metastatic UC. Previously, it was demonstrated that the membranous expression of Nectin-4 in bladder cancer cell lines is both necessary and sufficient for EV sensitivity in UC. An in vitro study showed that the resistance to EV is related to the downregulation of Nectin-4 in the tumor cell lines. However, in a recent clinical study, patients treated with EV initially benefitted from their treatment, but relapses appeared after multiple cycles of treatment. For some, membranous Nectin-4 expression was maintained in the metastasis after treatment. The mechanisms underlying the resistance to EV in UC with or without Nectin-4 downregulation are not fully understood. Due to discrepancies in findings regarding Nectin-4 expression and EV resistance, we hypothesize that multiple mechanisms are involved in the resistance to EV treatment in UC. We have recently developed in vitro models of EV resistance that maintained membranous levels of Nectin-4 expression comparable to the EV-sensitive controls. Currently, we are investigating the gene expression signature, DNA alterations and pathways dysregulation in EV-resistant cells. Our results will help to develop new strategies to overcome resistance to EV treatment in UC.

Scientific Focus Area: Cancer Biology

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