Non–Small Cell Lung Cancers with Kinase Domain Mutations in the Epidermal Growth Factor Receptor Are Sensitive to Ionizing Radiation
Autor: | Adi F. Gazdar, Luc Girard, Michael D. Story, Robert Graves, Michael Peyton, Mitsuo Sato, Stella Redpath, John D. Minna, Jerry W. Shay, Amit K. Das, Chaitanya S. Nirodi |
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Rok vydání: | 2006 |
Předmět: |
DNA Replication
Cancer Research Lung Neoplasms DNA Repair Recombinant Fusion Proteins Apoptosis medicine.disease_cause Radiation Tolerance T790M Gefitinib Growth factor receptor Carcinoma Non-Small-Cell Lung Tumor Cells Cultured medicine Humans Epidermal growth factor receptor Lung cancer Tumor Stem Cell Assay Sequence Deletion Mutation biology Exons Genes erbB-1 Genes p53 medicine.disease Beta Particles Neoplasm Proteins Protein Structure Tertiary respiratory tract diseases ErbB Receptors Oncology Drug Resistance Neoplasm Gamma Rays Quinazolines Cancer research biology.protein Erlotinib Tyrosine kinase medicine.drug |
Zdroj: | Cancer Research. 66:9601-9608 |
ISSN: | 1538-7445 0008-5472 |
Popis: | Non–small cell lung cancers (NSCLCs) bearing mutations in the tyrosine kinase domain (TKD) of the epidermal growth factor receptor (EGFR) often exhibit dramatic sensitivity to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. Ionizing radiation (IR) is frequently used in the treatment of NSCLC, but little is known how lung tumor–acquired EGFR mutations affect responses to IR. Because this is of great clinical importance, we investigated and found that clonogenic survival of mutant EGFR NSCLCs in response to IR was reduced 500- to 1,000-fold compared with wild-type (WT) EGFR NSCLCs. Exogenous expression of either the L858R point mutant or the ΔE746-E750 deletion mutant form of EGFR in immortalized human bronchial epithelial cells, p53 WT NSCLC (A549), or p53-null NSCLC (NCI-H1299) resulted in dramatically increased sensitivity to IR. We show that the majority of mutant EGFR NSCLCs, including those that contain the secondary gefitinib resistance T790M mutation, exhibit characteristics consistent with a radiosensitive phenotype, which include delayed DNA repair kinetics, defective IR-induced arrest in DNA synthesis or mitosis, and pronounced increases in apoptosis or micronuclei. Thus, understanding how activating mutations in the TKD domain of EGFR contribute to radiosensitivity should provide new insight into effective treatment of NSCLC with radiotherapy and perhaps avoid emergence of single agent drug resistance. (Cancer Res 2006; 66(19): 9601-07) |
Databáze: | OpenAIRE |
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