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

Abstract

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 5 355) and transcript levels were supportively determined based on gene expression microarray data from fresh-frozen NSCLC tissues (n 5 196). 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 5 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 5 0.03] and multivariate COX regression model (HR: 1.9; p 5 0.02). These findings encourage further clinical exploration of targeting ectopically activated CLDN expression as a valuable treatment concept in NSCLC.Non-small-cell lung cancer (NSCLC) therapy has changed dramatically as the comprehensive molecular analysis of lung cancer specimens has identified multiple, clinically relevant driver aberrations. Many of these aberrations can be targeted by specific inhibitors previously developed for the treatment of other cancer types.1,2 Indication extension of such drug

Claudin‐targeted drug development using anti‐claudin monoclonal antibodies to treat hepatitis and cancer

“…Determining the complex structures of other CLDNs and anti‐CLDN antibodies with proven pharmaceutical utility will promote theoretical in silico drug design for CLDN‐targeted drug development. In addition, clinical trials of anti‐CLDN antibodies as antitumor reagents are ongoing, and several groups are developing and screening new types of CLDN binders …”

“…In addition, clinical trials of anti-CLDN antibodies as antitumor reagents are ongoing, and several groups are developing and screening new types of CLDN binders. [88][89][90][91] Acknowledgments This work was supported by a Health and Labour Sciences Research grant from the Ministry of Health, Labour, and Welfare of Japan; a grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (24390042); a grant from the Adaptable and Seamless Technology Transfer Program through targetdriven R&D, Japan Science and Technology Agency; a grant from the platform for drug discovery, informatics, and structural life science of the Ministry of Education, Culture, Sports, Science, and Technology, Japan; a grant from the Japan Agency for Medical Research and Development; and the Takeda Science Foundation. Y.H.…”

CLDN18.1 attenuates malignancy and related signaling pathways of lung adenocarcinoma in vivo and in vitro

“…Another splicing isoform, CLDN18.2 , is normally expressed in stomach (10,11) and ectopically in pancreatic, esophageal, ovarian and lung cancers (12–14). Whereas numerous studies have focused on ectopic expression of CLDN18.2 , investigation of CLDN18.1 in cancer has been limited (15,16).…”

Displaying Tetra‐Membrane Spanning Claudins on Enveloped Virus‐Like Particles for Cancer Immunotherapy

“…Recent reports indicated the association of the claudin proteins CLDN18.2 and CLDN6 with different types of cancer . Claudins are tetra‐membrane spanning tight junction proteins often co‐localizing with members of the tetraspanin family building oligomeric protein layers in the membrane .…”