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Review
. 2024 Mar 28:14:1354543.
doi: 10.3389/fonc.2024.1354543. eCollection 2024.

Therapeutic prospects of nectin-4 in cancer: applications and value

Kaiyue Li #  1 , Yujing Zhou #  1 , Maolin Zang #  2 , Xin Jin  3 , Xin Li  1
Affiliations
Review

Therapeutic prospects of nectin-4 in cancer: applications and value

Kaiyue Li et al. Front Oncol. .

Abstract

Nectin-4 is a Ca2+-independent immunoglobulin-like protein that exhibits significantly elevated expression in malignant tumors while maintaining extremely low levels in healthy adult tissues. In recent years, overexpression of Nectin-4 has been implicated in tumor occurrence and development of various cancers, including breast cancer, urothelial cancer, and lung cancer. In 2019, the Food and Drug Administration approved enfortumab vedotin, the first antibody-drug conjugate targeting Nectin-4, for the treatment of urothelial carcinoma. This has emphasized the value of Nectin-4 in tumor targeted therapy and promoted the implementation of more clinical trials of enfortumab vedotin. In addition, many new drugs targeting Nectin-4 for the treatment of malignant tumors have entered clinical trials, with the aim of exploring potential new indications. However, the exact mechanisms by which Nectin-4 affects tumorigenesis and progression are still unclear, and the emergence of drug resistance and treatment-related adverse reactions poses challenges. This article reviews the diagnostic potential, prognostic significance, and molecular role of Nectin-4 in tumors, with a focus on clinical trials in the field of Nectin-4-related tumor treatment and the development of new drugs targeting Nectin-4.

Keywords: ADC; Nectin-4; biomarker; cancer; therapy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Biological function and structure of Nectin-4. The adhesion of nectins is Ca2+ independent, which is a homophilic and heterophilic process mediated by the outer domain through trans-interaction; the anchorage independence growth between tumor cells is achieved by PVRL4 through driving intercellular adhesion and stromal independent integrin-β4/SHP-2/c-Src activation, a process facilitated by the extracellular segment of Nectin-4; Nectin-4 can physically interact with importin-α2 to transfer to the nucleus to enhance DNA repair; the structure of Nectin-4 was shown in the right part of the figure.
Figure 2
Figure 2
the process of Nectin-4 regulating cancer development through PI3K/AKT pathway and promoting angiogenesis after hypoxia. Nectin-4 can downregulate miR-520c-3p to activate the PI3K/AKT/NF-κB pathway, promoting the progression and metastasis; Soluble nectin-4, which is formed by the shedding of Nectin-4 extracellular domain during hypoxia, can interact with integrin-β4 on endothelial cells to promote angiogenesis. This progress is realized via the Src, PI3K, Akt, and eNOS pathways, and may be related to PI3K-Akt-mediated NO formation.
Figure 3
Figure 3
the structure of EV and the process of destroying cancer cells. EV binds to Nectin-4 on the cell membrane, and the EV-antigen complex is internalized and transported along the endosomal pathway. In this process, various enzymes can incompletely hydrolyze EV, and finally EV is completely decomposed by lysosomes. The released MMAE will destabilize the microtubules, and the cells will undergo apoptosis due to the inhibition of division.
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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Natural Science Foundation of Shandong Province (ZR2022QH315).