Aberrantly activated claudin 6 and 18.2 as potential therapy targets in non‐small‐cell lung cancer

Claudins (CLDNs) are central components of tight junctions that regulate epithelial‐cell barrier function and polarity. Altered CLDN expression patterns have been demonstrated in numerous cancer types and lineage‐specific CLDNs have been proposed as therapy targets. The objective of this study was to assess which fraction of patients with non‐small‐cell lung cancer (NSCLC) express CLDN6 and CLDN18 isoform 2 (CLDN18.2). Protein expression of CLDN6 and CLDN18.2 was examined by immunohistochemistry on a tissue microarray ( n = 355) and transcript levels were supportively determined based on gene expression microarray data from fresh‐frozen NSCLC tissues ( n = 196). Both were analyzed with regard to frequency, distribution and association with clinical parameters. Immunohistochemical analysis of tissue sections revealed distinct membranous positivity of CLDN6 (6.5%) and CLDN18.2 (3.7%) proteins in virtually non‐overlapping subgroups of adenocarcinomas and large‐cell carcinomas. Pneumocytes and bronchial epithelial cells were consistently negative. Corresponding to the protein expression, in subsets of non‐squamous lung carcinoma high mRNA levels of CLDN6 (7–16%) and total CLDN18 (5–12%) were observed. Protein expression correlated well with total mRNA expression of the corresponding gene (rho = 0.4–0.8). CLDN18.2 positive tumors were enriched among slowly proliferating, thyroid transcription factor 1 (TTF‐1)‐negative adenocarcinomas, suggesting that isoform‐specific CLDN expression may delineate a specific subtype. Noteworthy, high CLDN6 protein expression was associated with worse prognosis in lung adenocarcinoma in the univariate [hazard ratio (HR): 1.8; p = 0.03] and multivariate COX regression model (HR: 1.9; p = 0.02). These findings encourage further clinical exploration of targeting ectopically activated CLDN expression as a valuable treatment concept in NSCLC.