Identification of Nectin-4 Oncoprotein as a Diagnostic and Therapeutic Target for Lung Cancer

Abstract

Gene expression profile analysis of lung cancers revealed the transactivation of an immunoglobulin-like molecule Nectin-4 in the majority of non-small cell lung cancers (NSCLC). Immunohistochemical staining of 422 NSCLCs showed that a high level of Nectin-4 expression was associated with poor prognosis for NSCLC patients (P < 0.0001), and multivariate analysis confirmed its independent prognostic value (P < 0.0001). We established an ELISA to measure serum Nectin-4 and found that serum Nectin-4 levels were significantly higher in NSCLC patients than in healthy volunteers. The proportion of the serum Nectin-4-positive cases was 88 of 164 (53.7%) NSCLCs, whereas only 3 of 131 (2.3%) healthy volunteers were falsely diagnosed as positive, which was superior to carcinoembryonic antigen (CEA) and cytokeratin 19-fragment (CYFRA21-1) in sensitivity and specificity. A combined ELISA for both Nectin-4 and CEA increased sensitivity and classified 65.0% of lung adenocarcinomas as positive with false-positive rate of 4.6%. The use of both Nectin-4 and CYFRA21-1 classified 68.3% of lung squamous cell carcinomas as positive with false-positive rate of 6.

Enfortumab Vedotin Antibody–Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models

“…Generally, we observed similar overall frequency of nectin-4 expression in ovarian cancer as previously published by Derycke and colleagues (26). Soluble form of Nectin-4 in patient serum and in ascites in case of ovarian cancer has been reported (24)(25)(26). Although the levels varied between reports, all investigators show an association between higher detected levels of soluble nectin-4 and disease progression.…”

“…More recently, nectin-4 was identified as an entry point for measles and other viruses and was proposed as a target for oncolytic viral therapy (21,22). Although several groups reported the detection of nectin-4 expression in breast, ovarian, and lung cancers (23)(24)(25)(26), no comprehensive analysis has been reported to date. Using suppression subtractive hybridization, we identified nectin-4 as one of the genes dramatically upregulated in bladder cancer specimens.…”

The Contribution of Ig-Superfamily and MARVEL D Tight Junction Proteins to Cancer Pathobiology

“…With accumulating data indicating occludin as an essential player in apoptotic signaling following TJ disruption and its downregulation predisposing to metastatic behaviors in vitro and in vivo, it is exciting to speculate that re-expressing occludin in cancer may act as a potential therapeutic target. In support, a previous in vitro study demonstrated how reexpression of occludin (in occludin-absent oncogene-transformed cells) was sufficient to restore the appearance of a normal epithelial phenotype (65). Though no clinical trials are currently underway, emerging research might potentially focus upon the epigenetic regulation of occludin via TTF-1 and other activators as a promising strategy to correct the deficits associated with occludin loss in cancer.…”

Expression of nectin-4 as a potential biomarker in enzootic nasal adenocarcinoma of goats

“…Normally, nectins 1, 2 and 3 show abundant expression in adult tissues, but nectin-4 is primarily expressed in the embryo and the placenta (Reymond et al, 2001;Fabre-Lafay et al, 2007). Nectin-4 has been shown to be a specific tumour-associated marker for ductal mammary carcinoma, lung adenocarcinoma and ovarian carcinoma in humans (Fabre-Lafay et al, 2007;Takano et al, 2009;Derycke et al, 2010). Studies in humans and experimental animal models have shown that nectin-4 is a valuable biomarker for evaluating tumour progression and the metastatic status of carcinomas (Fabre-Lafay et al, 2007;Oshima et al, 2013).…”

“…Nectin-4 is a type I transmembrane glycoprotein which has recently proven to be overexpressed in human breast carcinoma and is thus considered a specific tumour-associated marker, as the normal mammary gland lacks nectin-4 expression (Fabre-Lafay et al, 2007). In non-small cell lung cancer, a high level of nectin-4 expression has been shown to be associated with a poor prognosis (Takano et al, 2009). …”