Abstract IA4: Defining the mechanisms of tumorigenesis by mutant EGFR using mouse models
| Autor: | Katerina Politi |
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| Rok vydání: | 2012 |
| Předmět: | |
| Zdroj: | Clinical Cancer Research. 18:IA4-IA4 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Mutations in exons encoding the epidermal growth factor receptor (EGFR) are found in 10–15% of lung adenocarcinomas. The two most common mutations: a point mutation in exon 21 that leads to substitution of an arginine for a leucine at position 858 and small in-frame deletions in exon 19 are associated with sensitivity to the specific tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. Approximately 70% of tumors harboring EGFR mutations respond to treatment with these drugs, however 30% of these tumors exhibit primary resistance to treatment with these agents. Moreover, responses are transient and, on average, within a year of initiating treatment patients who initially respond eventually develop TKI-inhibitor-resistant disease. Drug resistance, in most cases, is due to a secondary mutation in EGFR (EGFR T790M). Other less frequent mechanisms of resistance include MET amplification, PIK3CA mutations and transformation to small cell lung cancer. However, the mechanism of resistance is still unknown in approximately 30% of cases. More effective treatment of patients with EGFR mutant lung cancer requires a better understanding of the mechanisms of primary and acquired resistance to EGFR TKIs and the development of strategies to overcome this resistance. To study these problems in vivo, we developed tetracycline-inducible transgenic mouse models of EGFR mutant lung cancer. Expression of lung cancer associated EGFR mutants gives rise to lung adenocarcinomas with bronchioloalveolar carcinoma features that are dependent upon the continuous activity of mutant EGFR for survival. Thus, treatment of the mice with erlotinib leads to tumor regression and long-term treatment with the drug gives rise to drug-resistant tumors that harbor some of the alterations observed in human TKI-resistant tumors such as the T790M mutation. Current efforts to use these mouse models to: 1) study mechanisms of primary and acquired resistance to EGFR TKIs and 2) evaluate new therapies to overcome resistance to first generation TKIs will be discussed. |
| Databáze: | OpenAIRE |
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