Nectin-4 significance in malignant neoplasms of the female reproductive system: a review of current data

Introduction. Nectin-4, a cell adhesion molecule of the immunoglobulin superfamily (IgSF), has been extensively studied in oncological diseases. Nectin-4 is involved in the formation of intercellular connections and promotes tumor cell proliferation, migration and chemoresistance. Upregulated nectin-4 expression has been detected in various malignant neoplasms, including tumors of the female reproductive system – ovarian, endometrial, cervical cancer, as well as rare tumors of the vulva, vagina and fallopian tubes.

Aim: to summarize current data on nectin-4 role in the pathogenesis, diagnostics, prognosis and therapy of malignant tumors of the female reproductive system, and to assess the prospects for its clinical use in personalized medicine.

Materials and Methods. A search for relevant publications was conducted in the PubMed/MEDLINE, Scopus, Web of Science, Embase and eLibrary.ru databases beginning from January 2000 to December 2024. The inclusion criteria covered original and review articles devoted to nectin-4 in gynecological oncology. Key words in Russian and English, Boolean operators, and filtering by full-text, subject matter, and quality of research were used. From the 3955 identified publications, 65 were included in the review.

Results. Nectin-4 expression is associated with enhanced tumor cell proliferation, migration, and chemoresistance, whereas its involvement in generating tight intercellular junctions promotes the development of chemoresistant spheroids. In ovarian cancer, upregulated levels of nectin-4 messenger RNA (mRNA) and serum protein demonstrated high diagnostic and prognostic significance, especially in combination with traditional markers such as cancer antigen 125 (CA-125). In endometrial cancer, nectin-4 expression correlates with a deficiency of the mismatch repair system (MMR genes) MSH2/MSH6 genes and lowered progression-free survival. In cervical carcinoma, nectin-4 is related to drug resistance, thereby positioning it as a promising target for novel treatment strategies. The latter using nanoquinacrine and antibody-drug conjugates (ADCs) such as 9MW2821 and ADRX-0706, are currently undergoing clinical trials. Additionally, nectin-4 has shown relevance in non-malignant reproductive disorders such as endometriosis and preeclampsia.

Conclusion. Nectin-4 demonstrates high clinical significance as a diagnostic and prognostic marker in gynecological malignancies. Its expression is associated with aggressive disease progression and drug resistance, especially in ovarian, endometrial and cervical cancers. Clinical trials with nectin-4-targeted drugs, including ADCs, are underway. Thus, nectin-4 represents a promising target for the development of personalized diagnostic and therapeutic strategies in gynecological oncology.

1. Averchenko R.R. Medical and social risk factors of oncogynecological pathology. [Mediko-social'nye risk-faktory vozniknoveniya onkoginekologicheskoj patologii]. Sovremennye problemy zdravoohraneniya i medicinskoj statistiki. 2024;(1);561–77. https://doi.org/10.24412/2312-2935-2024-1-561-577. (In Russ.).

2. Sabantsev M.A., Shramko S.V., Zhilina N.M. et al. Trends in incidence and prevalence of endometrial cancer in Russia and Novokuznetsk: a 2004-2021 study. [Rak endometriya: dinamika zabolevaemosti i rasprostranennosti za period 2004-2021 gg. v Rossii i Novokuznecke]. Byulleten' medicinskoj nauki. 2023;1(29):16–23. (In Russ.).

3. Saevets V. V., Vazhenin A.V., Ulrich E. A. et al. Diagnosis and treatment of common forms of stage III–IV ovarian cancer. [Diagnostika i lechenie rasprostranennyh form raka yaichnikov III–IV stadia]. Zlokachestvennye opuholi. 2020;10(3s1):15–20. (In Russ.). https://doi.org/10.18027/2224-5057-2019-10-3s1-15-20.

4. Kulieva G.Z., Mkrtchyan L.S., Krikunova L.I. et al. Epidemiological aspects of the incidence and mortality of cervical cancer (literature review). [Epidemiologicheskie aspekty zabolevaemosti rakom shejki matki i smertnosti ot nego (obzor literatury)]. Opuholi zhenskoj reproduktivnoj sistemy. 2023;19(3):77–84. (In Russ.). https://doi.org/10.17650/1994-4098-2023-19-3-77-84.

5. Safronova K.V., Artemyeva A.S., Nyuganen A.O. et al. Sarcomas of the lower female genital tract (vulva, vagina, and cervix): literature review and own cases. [Sarkomy nizhnego zhenskogo polovogo trakta (vul'vy, vlagalishcha i shejki matki): obzor literatury i sobstvennye nablyudeniya]. Opuholi zhenskoj reproduktivnoj sistemy. 2019;15(3):54–63. (In Russ.). https://doi.org/10.17650/1994-4098-2019-15-3-54-63.

6. Klyukina L.A., Sosnova E.A., Ishchenko A.A., Davydov M.M. The possibilities of predicting the individual risk of cervical cancer in women of reproductive age using mathematical modeling. [Vozmozhnosti prognozirovaniya individual'nogo riska razvitiya raka shejki matki u zhenshchin reproduktivnogo vozrasta s pomoshch'yu matematicheskogo modelirovaniya]. Opuholi zhenskoj reproduktivnoj sistemy. 2024;20(2):90–8. (In Russ.). https://doi.org/10.17650/1994-4098-2024-16-2-90-98.

7. Sadovaya ND, Bezmenko AA. There are strategies for screening and prevention of cervical cancer. [Strategii skrininga i profilaktiki raka shejki matki]. Izvestiya Rossijskoj voenno-medicinskoj akademii. 2024;43(1):77–85. (In Russ.). https://doi.org/10.17816/rmmar623153.

8. Semenkin A.A., Sapronenko V.S., Loginova E.N., Nadey E.V. Targeted therapy in oncology. [Targetnaya terapiya v onkologii]. Eksperimental'naya i klinicheskaya gastroenterologiya. 2022;9(205):222–8. (In Russ.). https://doi.org/10.31146/1682-8658-ecg-205-9-222-228.

9. Bodenko V.V., Larkina M.S., Prach A.A. et al. Molecular targets for metastasis-directed therapy in malignant tumors. [Molekulyarnye misheni targetnoj terapii zlokachestvennyh novoobrazovanij]. Byulleten' sibirskoj mediciny. 2024;23(2):101–13. (In Russ.). https://doi.org/10.20538/1682-0363-2024-2-101-113.

10. Pavlova N.N., Pallasch C., Elia A.E. et al. A role for PVRL4-driven cell-cell interactions in tumorigenesis. Elife. 2013;2:e00358. https://doi.org/10.7554/eLife.00358.

11. Shevlyuk N.N., Khalikova L.V., Khalikov A.A. et al. Participation of adhesion molecules in changing cell interactions during metastasis development. [Uchastie molekul adgezii v izmenenii vzaimodejstvij kletok pri razvitii metastazirovaniya]. Geny i Kletki. 2020;15(4):27–32. (In Russ.). https://doi.org/10.23868/202012004.

12. Samanta D., Almo S.C. Nectin family of cell-adhesion molecules: structural and molecular aspects of function and specificity. Cell Mol Life Sci. 2015;72(4):645–58. https://doi.org/10.1007/s00018-014-1763-4.

13. Miyoshi J., Takai Y. Nectin and nectin-like molecules: biology and pathology. Am J Nephrol. 2007;27(6):590–604. https://doi.org/10.1159/000108103.

14. Derycke M.S., Pambuccian S.E., Gilks C.B. et al. Nectin 4 overexpression in ovarian cancer tissues and serum: potential role as a serum biomarker. Am J Clin Pathol. 2010;134(5):835–45. https://doi.org/10.1309/AJCPGXK0FR4MHIHB.

15. Takai Y., Ikeda W., Ogita H., Rikitake Y. The immunoglobulin-like cell adhesion molecule nectin and its associated protein afadin. Annu Rev Cell Dev Biol. 2008;24:309–42. https://doi.org/10.1146/annurev.cellbio.24.110707.175339.

16. Liu Y., Han X., Li L. et al. Wang G. Role of Nectin-4 protein in cancer (Review). Int J Oncol. 2021;59(5):93. https://doi.org/10.3892/ijo.2021.5273.

17. Chatterjee S., Sinha S., Kundu C.N. Nectin cell adhesion molecule-4 (NECTIN-4): A potential target for cancer therapy. Eur J Pharmacol. 2021;911:174516. https://doi.org/10.1016/j.ejphar.2021.174516.

18. Fabre-Lafay S., Monville F., Garrido-Urbani S. et al. Nectin-4 is a new histological and serological tumor associated marker for breast cancer. BMC Cancer. 2007;7:73. https://doi.org/10.1186/1471-2407-7-73.

19. Liu Y., Li G., Zhang Y. et al. Nectin-4 promotes osteosarcoma progression and metastasis through activating PI3K/AKT/NF-κB signaling by down-regulation of miR-520c-3p. Cancer Cell Int. 2022;22(1):252. https://doi.org/10.1186/s12935-022-02669-w.

20. Deng H., Shi H., Chen L. et al. Over-expression of Nectin-4 promotes progression of esophageal cancer and correlates with poor prognosis of the patients. Cancer Cell Int. 2019;19:106. https://doi.org/10.1186/s12935-019-0824-z.

21. Takano A., Ishikawa N., Nishino R. et al. Identification of nectin-4 oncoprotein as a diagnostic and therapeutic target for lung cancer. Cancer Res. 2009;69(16):6694–703. https://doi.org/10.1158/0008-5472.CAN-09-0016.

22. Nishiwada S., Sho M., Yasuda S. et al. Nectin-4 expression contributes to tumor proliferation, angiogenesis and patient prognosis in human pancreatic cancer. J Exp Clin Cancer Res. 2015;34(1):30. https://doi.org/10.1186/s13046-015-0144-7.

23. Challita-Eid P.M., Satpayev D., Yang P. et al. Enfortumab vedotin antibody-drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res. 2016;76(10):3003–13. https://doi.org/10.1158/0008-5472.CAN-15-1313.

24. Boylan K.L.M., Manion R.D., Shah H. et al. Inhibition of ovarian cancer cell spheroid formation by synthetic peptides derived from nectin-4. Int J Mol Sci. 2020;21(13):4637. https://doi.org/10.3390/ijms21134637.

25. Chatterjee S., Kundu C.N. Nanoformulated quinacrine regulates NECTIN-4 domain specific functions in cervical cancer stem cells. Eur J Pharmacol. 2020;883:173308. https://doi.org/10.1016/j.ejphar.2020.173308.

26. Hoffman-Censits J., Maldonado L. Targeted treatment of locally advanced and metastatic urothelial cancer: enfortumab vedotin in context. Onco Targets Ther. 2022;15:1519–29. https://doi.org/10.2147/OTT.S370900.

27. Wu Y., Zhu M., Sun B. et al. A humanized trivalent Nectin-4-targeting nanobody drug conjugate displays potent antitumor activity in gastric cancer. J Nanobiotechnology. 2024;22(1):256. https://doi.org/10.1186/s12951-024-02521-5.

28. Pozharisskii K.M., Raskin G.A., Vinokurov V.L. et al. The immunohistochemical features of ovarian serous adenocarcinoma cells, which determine a disease course and survival rates in patients. [Immunogistohimicheskie osobennosti kletok seroznoj adenokarcinomy yaichnikov, opredelyayushchie klinicheskoe techenie zabolevaniya i vyzhivaemost' bol'nyh]. Arhiv patologii. 2015;77(1):38–40. (In Russ.). https://doi.org/10.17116/patol201577138.

29. Bekos C., Muqaku B., Dekan S. et al. NECTIN4 (PVRL4) as putative therapeutic target for a specific subtype of high grade serous ovarian cancer – an integrative multi-omics approach. Cancers (Basel). 2019;11(5):698. https://doi.org/10.3390/cancers11050698.

30. Klymenko Y., Nephew K.P. Epigenetic crosstalk between the tumor microenvironment and ovarian cancer cells: a therapeutic road less traveled. Cancers (Basel). 2018;10(9):295. https://doi.org/10.3390/cancers10090295.

31. Gong W., Liu Y., Diamandis E.P. et al. Prognostic value of kallikrein-related peptidase 7 (KLK7) mRNA expression in advanced high-grade serous ovarian cancer. J Ovarian Res. 2020;13(1):125. https://doi.org/10.1186/s13048-020-00725-5.

32. Dong Y., Loessner D., Irving-Rodgers H. et al. Metastasis of ovarian cancer is mediated by kallikrein related peptidases. Clin Exp Metastasis. 2014;31(1):135–47. https://doi.org/10.1007/s10585-013-9615-4.

33. Boylan K.L., Buchanan P.C., Manion R.D. et al. The expression of Nectin-4 on the surface of ovarian cancer cells alters their ability to adhere, migrate, aggregate, and proliferate. Oncotarget. 2017;8(6):9717–38. https://doi.org/10.18632/oncotarget.14206.

34. Nabih E.S., Motaleb F.I.A., Salama F.A. The diagnostic efficacy of nectin 4 expression in ovarian cancer patients. Biomarkers. 2014;19(6):498–504. https://doi.org/10.3109/1354750X.2014.940503.

35. Klinkebiel D., Zhang W., Akers S.N. et al. DNA methylome analyses implicate fallopian tube epithelia as the origin for high-grade serous ovarian cancer. Mol Cancer Res. 2016;14(9):787–94. https://doi.org/10.1158/1541-7786.MCR-16-0097.

36. Giancontieri P., Turetta C., Barchiesi G. et al. High-grade serous carcinoma of unknown primary origin associated with STIC clinically presented as isolated inguinal lymphadenopathy: a case report. Front Oncol. 2024;13:1307573. https://doi.org/10.3389/fonc.2023.1307573.

37. Rogmans C., Feuerborn J., Treeck L. et al. Nectin-4 as blood-based biomarker enables detection of early ovarian cancer stages. Cancers (Basel). 2022;14(23):5867. https://doi.org/10.3390/cancers14235867.

38. 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. Cell Oncol (Dordr). 2019;42(2):157–71. https://doi.org/10.1007/s13402-018-0417-1.

39. Satapathy S.R., Siddharth S., Das D. et al. Enhancement of cytotoxicity and inhibition of angiogenesis in oral cancer stem cells by a hybrid nanoparticle of bioactive quinacrine and silver: implication of base excision repair cascade. Mol Pharm. 2015;12(11):4011–25. https://doi.org/10.1021/acs.molpharmaceut.5b00461.

40. Das D., Satapathy S.R., Siddharth S. et al. NECTIN-4 increased the 5-FU resistance in colon cancer cells by inducing the PI3K-AKT cascade. Cancer Chemother Pharmacol. 2015;76(3):471–9. https://doi.org/10.1007/s00280-015-2794-8.

41. Nayak A., Satapathy S.R., Das D. et al. Nanoquinacrine induced apoptosis in cervical cancer stem cells through the inhibition of hedgehog-GLI1 cascade: role of GLI-1. Sci Rep. 2016;6:20600. https://doi.org/10.1038/srep20600.

42. Fang P., You M., Cao Y. et al. Development and validation of bioanalytical assays for the quantification of 9MW2821, a nectin-4-targeting antibody-drug conjugate. J Pharm Biomed Anal. 2024;248:116318. https://doi.org/10.1016/j.jpba.2024.116318.

43. Zhou W., Fang P., Yu D. et al. Preclinical evaluation of 9MW2821, a site-specific monomethyl auristatin E-based antibody-drug conjugate for treatment of Nectin-4-expressing cancers. Mol Cancer Ther. 2023;22(8):913–25. https://doi.org/10.1158/1535-7163.MCT-22-0743.

44. A phase 1a/b study ADRX-0706 in subjects with select advanced solid tumors. 2024. Available at: https://clinicaltrials.gov/study/NCT06036121. [Accessed: 23.02.2025].

45. Cancer Genome Atlas Research Network; Kandoth C., Schultz N., Cherniack A.D. et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73. https://doi.org/10.1038/nature12113.

46. Mahdy H., Vadakekut E.S., Crotzer D. Endometrial cancer. 2024 Apr 20. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing, 2025 Jan. 2024 Apr 20.

47. Brianso-Llort L., Saéz-Lopez C., Alvarez-Guaita A. et al. Recent advances on sex hormone-binding globulin regulation by nutritional factors: clinical implications. Mol Nutr Food Res. 2024;68(14):e2400020. https://doi.org/10.1002/mnfr.202400020.

48. Huang-Doran I., Kinzer A.B., Jimenez-Linan M. et al. Ovarian hyperandrogenism and response to gonadotropin-releasing hormone analogues in primary severe insulin resistance. J Clin Endocrinol Metab. 2021;106(8):2367–83. https://doi.org/10.1210/clinem/dgab275.

49. Wang L., Yang M., Guo X. et al. Estrogen-related receptor-α promotes gallbladder cancer development by enhancing the transcription of Nectin-4. Cancer Sci. 2020;111(5):1514–27. https://doi.org/10.1111/cas.14344.

50. Chen L., Mao X., Huang M. et al. PGC-1α and ERRα in patients with endometrial cancer: a translational study for predicting myometrial invasion. Aging (Albany NY). 2020;12(17):16963–80. https://doi.org/10.18632/aging.103611.

51. Chang H.K., Park Y.H., Choi J.A. et al. Nectin-4 as a predictive marker for poor prognosis of endometrial cancer with mismatch repair impairment. Cancers (Basel). 2023;15(10):2865. https://doi.org/10.3390/cancers15102865.

52. Bell D.W., Ellenson L.H. Molecular genetics of endometrial carcinoma. Annu Rev Pathol. 2019;14:339–67. https://doi.org/10.1146/annurev-pathol-020117-043609.

53. Calandrella M.L., Francesconi S., Caprera C. et al. Nectin-4 and DNA mismatch repair proteins expression in upper urinary tract urothelial carcinoma (UTUC) as a model for tumor targeting approaches: an ImGO pilot study. BMC Cancer. 2022;22(1):168. https://doi.org/10.1186/s12885-022-09259-z.

54. Dixit G., Gonzalez-Bosquet J., Skurski J. et al. FGFR2 mutations promote endometrial cancer progression through dual engagement of EGFR and Notch signalling pathways. Clin Transl Med. 2023;13(5):e1223. https://doi.org/10.1002/ctm2.1223.

55. Levchenko N.E., Mushtenko S.V., Savostikova M.V., Zakharova T.I. Problems of diagnostics and treatment of uterine tube cancer (clinical case). [Problemy diagnostiki i lecheniya raka matochnoj truby (klinicheskij sluchaj)]. Opuholi zhenskoj reproduktivnoj sistemy. 2016;12(3):80–6. (In Russ.). https://doi.org/10.17650/1994-4098-2016-12-3-80-86.

56. Lushnikova P.A., Sukhikh E.S., Startseva Zh.A. Vulvar cancer. The contribution of radiotherapy to the treatment of the disease. [Rak vul'vy. Vklad luchevoj terapii v lechenie zabolevaniya]. Sibirskij onkologicheskij zhurnal. 2024;23(3):150–8. (In Russ.). https://doi.org/10.21294/1814-4861-2024-23-3-150-158.

57. Kaltenecker B., Dunton C.J., Tikaria R. Vaginal Cancer. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing, 2025 Jan. 2023 Mar 1.

58. Gandhi T., Zubair M., Bhatt H. Cancer Antigen 125. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing, 2025 Jan. 2024 May 2.

59. Adamyan L.V, Andreeva E.N. Endometriosis and its global impact on a woman’s body. [Endometrioz i ego global'noe vliyanie na organizm zhenshchiny]. Problemy reprodukcii. 2022;28(1):54–64. (In Russ.). https://doi.org/10.17116/repro20222801154.

60. Bedir R., Sehitoglu I., Balik G. et al. The role of the adhesion molecule Nectin-4 in the pathogenesis of endometriosis. Clin Exp Obstet Gynecol. 2016;43(3):463–6.

61. Ballester M., Gonin J., Rodenas A. et al. Eutopic endometrium and peritoneal, ovarian and colorectal endometriotic tissues express a different profile of nectin-1, -3, -4 and nectin-like molecule 2. Hum Reprod. 2012;27(11):3179–86. https://doi.org/10.1093/humrep/des304.

62. Ito M., Nishizawa H., Tsutsumi M. et al. Potential role for nectin-4 in the pathogenesis of pre-eclampsia: a molecular genetic study. BMC Med Genet. 2018;19(1):166. https://doi.org/10.1186/s12881-018-0681-y.

63. Yoshizawa H., Nishizawa H., Ito M. et al. Increased levels of nectin-4 as a serological marker for pre-eclampsia. Fujita Med J. 2023;9(3):200–5. https://doi.org/10.20407/fmj.2022-027.

64. Grekova Yu.N., Zilberberg N.V., Kuznetsova E.I. Paget's extramammary disease. [Ekstramammarnaya bolezn' Pedzheta]. Akusherstvo i ginekologiya. 2022;(6):176–9. (In Russ.). https://doi.org/10.18565/aig.2022.6.176-179.

65. Murata M., Ito T., Tanaka Y. et al. NECTIN4 expression in extramammary Paget's disease: implication of a new therapeutic target. Int J Mol Sci. 2020;21(16):5891. https://doi.org/10.3390/ijms21165891.