A Novel Toll-Like Receptor 9 Agonist Cooperates with Trastuzumab in Trastuzumab-Resistant Breast Tumors through Multiple Mechanisms of Action
| Autor: | Ekambar R. Kandimalla, Sudhir Agrawal, Teresa Gelardi, Giampaolo Tortora, Vincenzo Damiano, Rosa Caputo, Luigi Racioppi, Corrado Garbi, Roberto Bianco, Sonia Garofalo, G. Merola, Roberta De Rosa |
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| Přispěvatelé: | Damiano, Vincenzo, Bianco, Roberto, Garofalo, Sonia, Rosa, Roberta, R., Caputo, Gelardi, Teresa, G., Merola, Racioppi, Luigi, Garbi, Corrado, Tortora, Giampaolo |
| Rok vydání: | 2009 |
| Předmět: |
endocrine system
Cancer Research Receptor ErbB-2 Oligonucleotides Angiogenesis Inhibitors Breast Neoplasms Pharmacology Antibodies Monoclonal Humanized resistance TLR9 Mice Breast cancer Trastuzumab HER2 medicine Animals Humans Epidermal growth factor receptor Neoplasm Metastasis skin and connective tissue diseases neoplasms trastuzumab Mice Inbred BALB C Tumor microenvironment biology business.industry Antibodies Monoclonal Cancer Middle Aged TLR-9 medicine.disease TRASTUZUMAB RESISTANCE Oncology Mechanism of action Drug Resistance Neoplasm Toll-Like Receptor 9 Cancer cell biology.protein Female Endothelium Vascular medicine.symptom Signal transduction business Neoplasm Transplantation medicine.drug |
| Zdroj: | Clinical Cancer Research. 15:6921-6930 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-09-1599 |
| Popis: | Purpose: Resistance to anti-HER2 monoclonal antibody trastuzumab is a relevant issue in breast cancer patients. Among the mechanisms implicated in trastuzumab resistance, increasing evidence supports a role of tumor microenvironment. We previously found that a novel toll-like receptor 9 agonist, referred to as immune modulatory oligonucleotide (IMO) and currently under clinical investigation, acts through epidermal growth factor receptor (EGFR) and shows direct antiangiogenic effects by cooperating with anti-EGFR or anti-VEGF drugs, thus interfering with cancer cells and microenvironment.Experimental Design: In this study, we used KPL-4 and JIMT-1 trastuzumab-resistant breast cancer cells to evaluate the combination IMO plus trastuzumab as a therapeutic option for trastuzumab-resistant breast cancers.Results: IMO inhibits KPL-4 and JIMT-1 xenografts growth and potentiates trastuzumab antitumor effect, with complete suppression of tumor growth, potent enhancement of trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity, and strong inhibition of EGFR/HER2-related signaling. In KPL-4 xenografts, IMO alone interferes with HER signal transduction, whereas trastuzumab is ineffective. IMO induces an HER-dependent signal inhibition also in vitro by modulating a functional interaction between toll-like receptor 9 and HER receptors occurring at membrane level. Finally, IMO plus trastuzumab produces a cooperative antiangiogenic effect related to suppression of endothelial HER-related signaling.Conclusions: We showed a cooperative effect of IMO plus trastuzumab in trastuzumab-resistant breast cancers due to IMO direct antitumor and antiangiogenic activity and antibody-dependent cell-mediated cytotoxicity enhancement. Moreover, we provided first evidence of a toll-like receptor 9/HER interaction at membrane level as novel mechanism of action. Altogether, we propose IMO plus trastuzumab as an effective strategy in trastuzumab-resistant breast cancers. (Clin Cancer Res 2009;15(22):692130) |
| Databáze: | OpenAIRE |
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