ArticleCell & bioscience2023
Improving the response to oxaliplatin by targeting chemotherapy-induced CLDN1 in resistant metastatic colorectal cancer cells.
Article in Cell & bioscience, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 21 citations in OpenAlex.
- Mechanisms and advances of drug resistance in colorectal cancer: A systematic overview of multi-layered regulatory networks.Translational oncology · 2026Review
- Claudin proteins as emerging therapeutic targets for solid tumours.Nature reviews. Cancer · 2026Review
- ULK1 promotes oxaliplatin resistance of colon cancer via phosphorylation of Bax S184.British journal of cancer · 2026Article
- Antibody-drug conjugates in colorectal cancer: advances in targeted delivery and personalized oncology.Frontiers in bioengineering and biotechnology · 2026Review
- Enhancing targeted delivery and efficacy of PEGylated liposomal doxorubicin with liposomal minoxidil: comprehensive in silico, in vitro, and in vivo tumor model studies.Drug delivery · 2025Article
- TopBP1 biomolecular condensates as a new therapeutic target in advanced-stage colorectal cancer.eLife · 2025Article
- Prognostic Significance ofBiomedicines · 2025Article
- Insights and implications for transcriptomic analysis of heat stress-induced intestinal inflammation in pigs.BMC genomics · 2024Article
- Micro RNA-175 TargetsGenes · 2024Article
- Tight Junctions and Cancer: Targeting Claudin-1 and Claudin-4 in Thyroid Pathologies.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Why Is Wnt/β-Catenin Not Yet Targeted in Routine Cancer Care?Pharmaceuticals (Basel, Switzerland) · 2024Review
- Antibody-mediated targeting of Claudins in cancer.Frontiers in oncology · 2024Review
- Claudin-1 interacts with EPHA2 to promote cancer stemness and chemoresistance in colorectal cancer.Cancer letters · 2023Article
- Expression of Claudin-9 (CLDN9) in Breast Cancer, the Clinical Significance in Connection with Its Subcoat Anchorage Proteins ZO-1 and ZO-3 and Impact on Drug Resistance.Biomedicines · 2023Article
- Tight Junction Claudins and Occludin Are Differentially Regulated and Expressed in Genomically Defined Subsets of Colon Cancer.Current issues in molecular biology · 2023Article
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Authors and funding
19 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundTumor resistance is a frequent cause of therapy failure and remains a major challenge for the long-term management of colorectal cancer (CRC). The aim of this study was to determine the implication of the tight junctional protein claudin 1 (CLDN1) in the acquired resistance to chemotherapy.
methodsImmunohistochemistry was used to determine CLDN1 expression in post-chemotherapy liver metastases from 58 CRC patients. The effects of oxaliplatin on membrane CLDN1 expression were evaluated by flow cytometry, immunofluorescence and western blotting experiments in vitro and in vivo. Phosphoproteome analyses, proximity ligation and luciferase reporter assays were used to unravel the mechanism of CLDN1 induction. RNAseq experiments were performed on oxaliplatin-resistant cell lines to investigate the role of CLDN1 in chemoresistance. The "one-two punch" sequential combination of oxaliplatin followed by an anti-CLDN1 antibody-drug conjugate (ADC) was tested in both CRC cell lines and murine models.
resultsWe found a significant correlation between CLDN1 expression level and histologic response to chemotherapy, CLDN1 expression being the highest in resistant metastatic residual cells of patients showing minor responses. Moreover, in both murine xenograft model and CRC cell lines, CLDN1 expression was upregulated after exposure to conventional chemotherapies used in CRC treatment. CLDN1 overexpression was, at least in part, functionally related to the activation of the MAPKp38/GSK3β/Wnt/β-catenin pathway. Overexpression of CLDN1 was also observed in oxaliplatin-resistant CRC cell lines and was associated with resistance to apoptosis, suggesting an anti-apoptotic role for CLDN1. Finally, we demonstrated that the sequential treatment with oxaliplatin followed by an anti-CLDN1 ADC displayed a synergistic effect in vitro and in in vivo.
conclusionOur study identifies CLDN1 as a new biomarker of acquired resistance to chemotherapy in CRC patients and suggests that a "one-two punch" approach targeting chemotherapy-induced CLDN1 expression may represent a therapeutic opportunity to circumvent resistance and to improve the outcome of patients with advanced CRC.
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