Erlotinib is a viable treatment for tumors with acquired resistance to cetuximab
| Autor: | Chunrong Li, Toni M. Brand, Mari Iida, Chimera R. Peet, Rebecca A. Myers, Deric L. Wheeler, Kellie T. Kostopoulos, Emily F. Dunn |
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| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Receptor ErbB-2 Cetuximab Mice Nude Antineoplastic Agents Apoptosis Pharmacology Antibodies Monoclonal Humanized Lapatinib Erlotinib Hydrochloride Mice Gefitinib Cell Line Tumor medicine Animals Humans Epidermal growth factor receptor RNA Small Interfering neoplasms Cell Proliferation EGFR inhibitors biology business.industry Antibodies Monoclonal Xenograft Model Antitumor Assays digestive system diseases respiratory tract diseases ErbB Receptors Oncology Drug Resistance Neoplasm Quinazolines Cancer research biology.protein Molecular Medicine RNA Interference Erlotinib Mitogen-Activated Protein Kinases business Proto-Oncogene Proteins c-akt Tyrosine kinase Research Paper medicine.drug |
| Zdroj: | Cancer Biology & Therapy. 12:436-446 |
| ISSN: | 1555-8576 1538-4047 |
| DOI: | 10.4161/cbt.12.5.16394 |
| Popis: | The epidermal growth factor receptor (EGFR) is a ubiquitously expressed receptor tyrosine kinase (RTK) and is recognized as a key mediator of tumorigenesis in many human tumors. Currently there are five EGFR inhibitors used in oncology, two monoclonal antibodies (panitumumab, and cetuximab) and three tyrosine kinase inhibitors (erlotinib, gefitinib, and lapatinib). Both strategies of EGFR inhibition have demonstrated clinical successes, however many tumors remain non-responsive or acquire resistance during therapy. To explore potential molecular mechanisms of acquired resistance to cetuximab we previously established a series of cetuximab-resistant clones by chronically exposing the NCI-H226 NSCLC cell line to escalating doses of cetuximab. Cetuximab-resistant clones exhibited a dramatic increase in steady-state expression of EGFR, HER2, and HER3 receptors as well as increased signaling through the MAPK and AKT pathways. RNAi studies demonstrated dependence of cetuximab-resistant clones on the EGFR signaling network. These findings prompted investigation on whether or not cells with acquired resistance to cetuximab would be sensitive to the EGFR targeted TKI erlotinib. In vitro, erlotinib was able to decrease signaling through the EGFR axis, decrease cellular proliferation, and induce apoptosis. To determine if erlotinib could have therapeutic benefit in vivo, we established cetuximab-resistant NCI-H226 mouse xenografts, and subsequently treated them with erlotinib. Mice harboring cetuximab-resistant tumors treated with erlotinib exhibited either a tumor regression or growth delay as compared to vehicle controls. Analysis of the erlotinib treated tumors demonstrated a decrease in cell proliferation and increase rates of apoptosis. The work presented herein suggests that 1) cells with acquired resistance to cetuximab maintain their dependence on EGFR and 2) tumors developing resistance to cetuximab can benefit from subsequent treatment with erlotinib, providing rationale for its use in the setting of cetuximab resistance. |
| Databáze: | OpenAIRE |
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