AZD9291 Increases Sensitivity to Radiation in PC-9-IR Cells by Delaying DNA Damage Repair after Irradiation and Inducing Apoptosis
| Autor: | Sumei Chen, Jingjing Zhang, Shirong Zhang, Shenghai Wu, Ma Shenglin, Lucheng Zhu, Linglan Tu, Haixiu Huang |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Lung Neoplasms Time Factors DNA Repair DNA repair medicine.drug_class Biophysics Apoptosis Radiation Tolerance Tyrosine-kinase inhibitor 03 medical and health sciences T790M Mice 0302 clinical medicine Gefitinib Carcinoma Non-Small-Cell Lung Cell Line Tumor medicine Animals Humans Radiology Nuclear Medicine and imaging Epidermal growth factor receptor Lung cancer Extracellular Signal-Regulated MAP Kinases Protein kinase B Cell Proliferation Acrylamides Radiation Aniline Compounds biology Dose-Response Relationship Drug Chemistry Cell growth medicine.disease Xenograft Model Antitumor Assays respiratory tract diseases Enzyme Activation ErbB Receptors 030104 developmental biology 030220 oncology & carcinogenesis Mutation Cancer research biology.protein Female Proto-Oncogene Proteins c-akt medicine.drug |
| Zdroj: | Radiation research. 189(3) |
| ISSN: | 1938-5404 |
| Popis: | AZD9291 is a novel, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), which is administered orally. It has been proven effective in non-small cell lung cancer (NSCLC) patients, with both EGFR-sensitizing and EGFR T790M mutations in preclinical models. However, the potential therapeutic effects of AZD9291 combined with other modalities, including ionizing radiation, are not well understood. The presence of AZD9291 significantly increases the cell-killing effects of radiation in PC-9-IR cells with a secondary EGFR mutation (T790M), which was developed from NSCLC PC-9 cells (human lung adenocarcinoma cell with EGFR 19 exon 15 bp deletion) after chronic exposure to increasing doses of gefitinib, and in H1975 cells (human lung adenocarcinoma cell with EGFR exon 20 T790M mutation de novo), but not in PC-9 cells or in H460 cells (human lung adenocarcinoma cell with wild-type EGFR). In PC-9-IR cells, AZD9291 remarkably decreases phosphorylation levels of EGFR, extracellular regulated protein kinase (ERK), and protein kinase B (AKT). AZD9291 increases sensitivity to radiation in PC-9-IR cells by delaying deoxyribonucleic acid (DNA) damage repair after irradiation and inducing apoptosis, and enhances tumor growth inhibition when combined with radiation in PC-9-IR xenografts. Our findings suggest a potential therapeutic effect of AZD9291 as a radiation sensitizer in lung cancer cells with an acquired EGFR T790M mutation, providing a rationale for a clinical trial using the combination of AZD9291 and radiation in NSCLCs harboring acquired T790M mutation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|