Research Progress of Nectin-4 in Gynecologic Malignancies

doi:10.12280/gjfckx.20250043

Abstract

Abstract:

Nectin-4 is a tumor-associated cell adhesion molecule that is highly expressed in various gynecologic malignancies, such as cervical, ovarian, and endometrial cancers, and is closely related to tumor development, progression, and prognosis. In recent years, Nectin-4 has emerged as an important target for the development of antibody-drug conjugate (ADC). Enfortumab vedotin (EV), an ADC targeting Nectin-4, has been approved by the US Food and Drug Administration (FDA) for the treatment of urothelial cancer. However, no clinical trials have directly evaluated the application of EV in gynecologic malignancies. Nevertheless, multiple studies have shown that the high expression of Nectin-4 in gynecologic malignancies may make it a potential therapeutic target. In addition, domestic ADCs such as 9MW2821 and SHR-A2102 are currently in clinical trials and are expected to offer new treatment options for gynecologic malignancies. Future studies on the efficacy and safety of Nectin-4-targeted ADCs in gynecologic malignancies are highly anticipated and may bring new hope to patients with drug resistant or advanced disease.

Key words: Nectins, Genital neoplasms, female, Immunoconjugates, Molecular targeted therapy, Nectin-4, Enfortumab vedotin

ZHANG Hao-sheng, WEI Fang. Research Progress of Nectin-4 in Gynecologic Malignancies[J]. Journal of International Obstetrics and Gynecology, 2025, 52(2): 165-168.

References 27

[1]	Wang H, Sun D, Chen J, et al. Nectin-4 has emerged as a compelling target for breast cancer[J]. Eur J Pharmacol, 2023, 960:176129. doi: 10.1016/j.ejphar.2023.176129.
[2]	Nanamiya T, Takane K, Yamaguchi K, et al. Expression of PVRL4, a molecular target for cancer treatment, is transcriptionally regulated by FOS[J]. Oncol Rep, 2024, 51(1):17. doi: 10.3892/or.2023.8676.
[3]	首都医科大学肿瘤学系妇科肿瘤学组, 白文佩. 妇科常见恶性肿瘤全专结合管理专家共识[J]. 中国全科医学, 2025, 28(8):911-922. doi: 10.12114/j.issn.1007-9572.2024.0204.
[4]	Heath EI, Rosenberg JE. The biology and rationale of targeting nectin-4 in urothelial carcinoma[J]. Nat Rev Urol, 2021, 18(2):93-103. doi: 10.1038/s41585-020-00394-5. pmid: 33239713
[5]	Moussa M, Papatsoris A, Abou Chakra M, et al. Profile of Enfortumab Vedotin in the Treatment of Urothelial Carcinoma: The Evidence to Date[J]. Drug Des Devel Ther, 2021, 15:453-462. doi: 10.2147/DDDT.S240854.
[6]	Chatterjee S, Sinha S, Kundu CN. Nectin cell adhesion molecule-4 (NECTIN-4): A potential target for cancer therapy[J]. Eur J Pharmacol, 2021, 911:174516. doi: 10.1016/j.ejphar.2021.174516.
[7]	万洋洋, 接晶, 陶国华. Nectin 4在乳腺癌中的表达及其临床意义[J]. 交通医学, 2021, 35(1):13-16. doi: 10.19767/j.cnki.32-1412.2021.01.004.
[8]	Sethy C, Goutam K, Das B, et al. Nectin-4 promotes lymphangiogenesis and lymphatic metastasis in breast cancer by regulating CXCR4-LYVE-1 axis[J]. Vascul Pharmacol, 2021, 140:106865. doi: 10.1016/j.vph.2021.106865.
[9]	Hoffman-Censits JH, Lombardo KA, Parimi V, et al. Expression of Nectin-4 in Bladder Urothelial Carcinoma, in Morphologic Variants, and Nonurothelial Histotypes[J]. Appl Immunohistochem Mol Morphol, 2021, 29(8):619-625. doi: 10.1097/PAI.0000000000000938. pmid: 33901032
[10]	Kobecki J, Gajdzis P, Mazur G, et al. Prognostic Potential of Nectin Expressions in Colorectal Cancer: An Exploratory Study[J]. Int J Mol Sci, 2023, 24(21):15900. doi: 10.3390/ijms242115900.
[11]	Toda S, Sato S, Saito N, et al. TROP-2, Nectin-4, GPNMB, and B7-H3 Are Potentially Therapeutic Targets for Anaplastic Thyroid Carcinoma[J]. Cancers(Basel), 2022, 14(3):579. doi: 10.3390/cancers14030579.
[12]	Tanaka Y, Murata M, Shen CH, et al. NECTIN4: A Novel Therapeutic Target for Melanoma[J]. Int J Mol Sci, 2021, 22(2):976. doi: 10.3390/ijms22020976.
[13]	Li K, Zhou Y, Zang M, et al. Therapeutic prospects of nectin-4 in cancer: applications and value[J]. Front Oncol, 2024, 14:1354543. doi: 10.3389/fonc.2024.1354543.
[14]	Bruce JY, Pusztai L, Braiteh F, et al. EV-202: A phase Ⅱ study of enfortumab vedotin in patients with select previously treated locally advanced or metastatic solid tumors[J]. J Clinic Oncol, 2020, 38(suppl 15):tps3647. doi: 10.1200/JCO.2020.38.15_suppl.TPS3647.
[15]	Nieto-Jiménez C, Sanvicente A, Díaz-Tejeiro C, et al. Uncovering therapeutic opportunities in the clinical development of antibody-drug conjugates[J]. Clin Transl Med, 2023, 13(9):e1329. doi: 10.1002/ctm2.1329. pmid: 37740463
[16]	Shen S, Zhang S, Liu P, et al. Potential role of microRNAs in the treatment and diagnosis of cervical cancer[J]. Cancer Genet, 2020, 248/249:25-30. doi: 10.1016/j.cancergen.2020.09.003.
[17]	Sharma S, Deep A, Sharma AK. Current Treatment for Cervical Cancer: An Update[J]. Anticancer Agents Med Chem, 2020, 20(15):1768-1779. doi: 10.2174/1871520620666200224093301.
[18]	Nayak A, Das S, Nayak D, et al. Nanoquinacrine sensitizes 5-FU-resistant cervical cancer stem-like cells by down-regulating Nectin-4 via ADAM-17 mediated NOTCH deregulation[J]. Cell Oncol(Dordr), 2019, 42(2):157-171. doi: 10.1007/s13402-018-0417-1.
[19]	Chatterjee S, Kundu CN. Nanoformulated quinacrine regulates NECTIN-4 domain specific functions in cervical cancer stem cells[J]. Eur J Pharmacol, 2020, 883:173308. doi: 10.1016/j.ejphar.2020.173308.
[20]	Richardson DL, Eskander RN, O′Malley DM. Advances in Ovarian Cancer Care and Unmet Treatment Needs for Patients With Platinum Resistance: A Narrative Review[J]. JAMA Oncol, 2023, 9(6):851-859. doi: 10.1001/jamaoncol.2023.0197.
[21]	Morand S, Devanaboyina M, Staats H, et al. Ovarian Cancer Immunotherapy and Personalized Medicine[J]. Int J Mol Sci, 2021, 22(12):6532. doi: 10.3390/ijms22126532.
[22]	Rogmans C, Feuerborn J, Treeck L, et al. Nectin-4 as Blood-Based Biomarker Enables Detection of Early Ovarian Cancer Stages[J]. Cancers(Basel), 2022, 14(23):5867. doi: 10.3390/cancers14235867.
[23]	Boylan KL, Buchanan PC, Manion RD, et al. The expression of Nectin-4 on the surface of ovarian cancer cells alters their ability to adhere, migrate, aggregate, and proliferate[J]. Oncotarget, 2017, 8(6):9717-9738. doi: 10.18632/oncotarget.14206. pmid: 28038455
[24]	Boylan K, Manion RD, Shah H, et al. Inhibition of Ovarian Cancer Cell Spheroid Formation by Synthetic Peptides Derived from Nectin-4[J]. Int J Mol Sci, 2020, 21(13):4637. doi: 10.3390/ijms21134637.
[25]	Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6):394-424. doi: 10.3322/caac.21492.
[26]	Chang HK, Park YH, Choi JA, et al. Nectin-4 as a Predictive Marker for Poor Prognosis of Endometrial Cancer with Mismatch Repair Impairment[J]. Cancers(Basel), 2023, 15(10):2865. doi: 10.3390/cancers15102865.
[27]	Karpel HC, Powell SS, Pothuri B. Antibody-Drug Conjugates in Gynecologic Cancer[J]. Am Soc Clin Oncol Educ Book, 2023, 43:e390772. doi: 10.1200/EDBK_390772.