Novel Toll-Like Receptor 9 Agonist Induces Epidermal Growth Factor Receptor (EGFR) Inhibition and Synergistic Antitumor Activity with EGFR Inhibitors
| Autor: | Sudhir Agrawal, Francesco Paolo D'Armiento, Vincenzo Damiano, Sabino De Placido, Antonio Leonardi, A. Raffaele Bianco, Fortunato Ciardiello, Giampaolo Tortora, Rosa Caputo, Roberto Bianco |
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| Rok vydání: | 2006 |
| Předmět: |
Vascular Endothelial Growth Factor A
endocrine system Cancer Research medicine.drug_class Angiogenesis Transplantation Heterologous Oligonucleotides Cetuximab Mice Nude Antineoplastic Agents Antibodies Monoclonal Humanized Tyrosine-kinase inhibitor Mice Gefitinib Growth factor receptor medicine Animals Humans Epidermal growth factor receptor Protein kinase B Cell Proliferation EGFR inhibitors Mice Inbred BALB C Neovascularization Pathologic biology NF-kappa B Antibodies Monoclonal Drug Synergism ErbB Receptors Proto-Oncogene Proteins c-bcl-2 Oncology Cyclooxygenase 2 Drug Resistance Neoplasm Toll-Like Receptor 9 Colonic Neoplasms Cancer research biology.protein Drug Therapy Combination Mitogen-Activated Protein Kinases Proto-Oncogene Proteins c-akt Signal Transduction medicine.drug |
| Zdroj: | Clinical Cancer Research. 12:577-583 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-05-1943 |
| Popis: | Purpose: Immunostimulating Toll-like receptor 9 (TLR9) agonists cause antitumor activity interfering also with cancer proliferation and angiogenesis by mechanisms still incompletely understood. We hypothesized that modified TLR9 agonists could impair epidermal growth factor receptor (EGFR) signaling and, by this means, greatly enhance EGFR inhibitors effect, acting on both the receptor targeting and the immunologic arm. Experimental Design: We used a novel second-generation, modified, immunomodulatory TLR9 agonist (IMO), alone and in combination with the anti-EGFR monoclonal antibody cetuximab or tyrosine kinase inhibitor gefitinib, on the growth of GEO and cetuximab-resistant derivatives GEO-CR colon cancer xenografts. We have also evaluated the expression of several proteins critical for cell proliferation, apoptosis, and angiogenesis, including EGFR, mitogen-activated protein kinase, Akt, bcl-2, cyclooxygenase-2, vascular endothelial growth factor, and nuclear factor-κB. Results: IMO inhibited GEO growth and signaling by EGFR and the other proteins critical for cell proliferation and angiogenesis. IMO plus the anti-EGFR antibody cetuximab synergistically inhibited tumor growth, signaling proteins, and microvessel formation. EGFR signaling inhibition by IMO is relevant because IMO cooperated also with EGFR tyrosine kinase inhibitor gefitinib in GEO tumors, while it was inactive against GEO-CR xenografts. On the other hand, IMO boosted the non-EGFR-dependent cetuximab activity, causing a cooperative antitumor effect in GEO-CR cells. Finally, combination of IMO, cetuximab and chemotherapeutic irinotecan eradicated the tumors in 90% of mice. Conclusion: IMO interferes with EGFR-related signaling and angiogenesis and has a synergistic antitumor effect with EGFR inhibitors, especially with cetuximab, boosting both the EGFR dependent and independent activity of this agent. Moreover, this therapeutic strategy could be translated in patients affected by colorectal cancer. |
| Databáze: | OpenAIRE |
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