Targeted therapeutic strategies for Nectin-4 in breast cancer: Recent advances and future prospects

Abstract

Nectin-4 is a cell adhesion molecule which has gained more and more attention as a therapeutic target in cancer recently. Overexpression of Nectin-4 has been observed in various tumors, including breast cancer, and is associated with tumor progression. Enfortumab vedotin(EV)is an antibody-drug conjugate (ADC) targeting Nectin-4, which has been approved by FDA for the treatment of urothelial carcinoma. Notably, Nectin-4 was also investigated as a target for breast cancer in preclinical and clinical settings. Nectin-4-targeted approaches, such as ADCs, oncolytic viruses, photothermal therapy and immunotherapy, have shown promising results in early-phase clinical trials. These therapies offer novel strategies for delivering targeted treatments to Nectin-4-expressing cancer cells, enhancing treatment efficacy and minimizing off-target effects. In conclusion, this review aims to provide an overview of the latest advances in understanding the role of Nectin-4 in breast cancer and discuss the future development prospects of Nectin-4 targeted agents.

Keywords: Antibody drug conjugates (ADCs); Breast cancer; Enfortumab vedotin (EV); Nectin-4; Targeted therapy.

Graphical abstract

Fig. 1

The role of Nectin-4 in cancer. The internal part of Nectin-4 binds to the PDZ domain of afadin. Up-regulated Nectin-4 can interact with afadin and activate Rac1 through the PI3K/AKT pathway, promoting tumor growth, migration, and epithelial-mesenchymal transition (EMT). ADAM-17 specifically cleaves Nectin-4 into the extracellular and intracellular domains under hypoxia. The intracellular segment is translocated into the nucleus, where it participates in DNA repair and promotes cell survival. The extracellular segment binds to the Integrin-β of vascular endothelial cells and promotes angiogenesis through the PI3K-AKT-mediated endothelial nitric oxide synthase (eNOS) pathway. In addition, the extracellular segment activates lymphatic endothelial receptor 1 (LYVE-1)-mediated lymphangiogenesis by interacting with CXCR4/CXCL12. Created with BioRender.

Fig. 2

The mechanisms of targeting Nectin-4. (A) ADC binds Nectin-4 and is internalized by tumor cells, releasing cytotoxic substances and leading to cell apoptosis. (B) Oncolytic viruses targeting nectin-4 are endocytosed into tumor cells, leading to cell lysis through replication and expression. (C) The interaction of TIGIT and Nectin-4 can transmit inhibitory signals through ITIM domains and immunoglobulin tyrosine tail (ITT)-like motifs. Blocking Nectin-4 and TIGIT specific binding can activate T/NK cells. (D) Photothermal therapy (PTT) targeting Nectin-4 can deliver photothermal agents (PTA) to tumor cells with high Nectin-4 expression, thereby killing tumor cells under near-infrared (NIR) light. Created with BioRender.

Fig. 3

Combination therapy of ADCs targeting Nectin-4. Created with BioRender.