Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer
| Autor: | Lewis C. Cantley, George N. Naumov, John V. Heymach, Ana M. Borras, Bruce E. Johnson, Christopher Michael Gale, Toru Mukohara, Emily T Jarrell, Beow Y. Yeap, Pasi A. Jänne, Jeffrey A. Engelman, Jason Sun, Kreshnik Zejnullahu, Sean Tracy, Xiaojun Zhao, Eugene Lifshits |
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| Rok vydání: | 2006 |
| Předmět: |
Lung Neoplasms
Receptor ErbB-3 Mutant Mutation Missense Apoptosis Biology Transfection medicine.disease_cause Mice Phosphatidylinositol 3-Kinases T790M Gefitinib Cell Line Tumor medicine Animals Humans heterocyclic compounds Phosphorylation Extracellular Signal-Regulated MAP Kinases skin and connective tissue diseases Lung cancer Protein Kinase Inhibitors neoplasms Alleles Cell Proliferation EGFR inhibitors Mutation Base Sequence Gene Amplification General Medicine medicine.disease Resistance mutation Xenograft Model Antitumor Assays Molecular biology respiratory tract diseases ErbB Receptors Drug Resistance Neoplasm Quinazolines Cancer research RNA Interference Erlotinib Proto-Oncogene Proteins c-akt Research Article medicine.drug |
| Zdroj: | Journal of Clinical Investigation. 116:2695-2706 |
| ISSN: | 0021-9738 |
| Popis: | EGFR is frequently mutated and amplified in lung adenocarcinomas sensitive to EGFR inhibitors gefitinib and erlotinib. A secondary mutation, T790M, has been associated with acquired resistance but has not been shown to be sufficient to render EGFR mutant/amplified lung cancers resistant to EGFR inhibitors. We created a model for studying acquired resistance to gefitinib by prolonged exposure of a gefitinib-sensitive lung carcinoma cell line (H3255; EGFR mutated and amplified) to gefitinib in vitro. The resulting resistant cell line acquired a T790M mutation in a small fraction of the amplified alleles that was undetected by direct sequencing and identified only by a highly sensitive HPLC-based technique. In gefitinib-sensitive lung cancer cells with EGFR mutations and amplifications, exogenous introduction of EGFR T790M effectively conferred resistance to gefitinib and continued ErbB-3/PI3K/Akt signaling when in cis to an activating mutation. Moreover, continued activation of PI3K signaling by the PIK3CA oncogenic mutant, p110alpha E545K, was sufficient to abrogate gefitinib-induced apoptosis. These findings suggest that allelic dilution of biologically significant resistance mutations may go undetected by direct sequencing in cancers with amplified oncogenes and that restoration of PI3K activation via either a T790M mutation or other mechanisms can provide resistance to gefitinib. |
| Databáze: | OpenAIRE |
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