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Afatinib increases sensitivity to radiation in non-small cell lung cancer cells with acquired EGFR T790M mutation
Afatinib is a second-generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and has shown a significant clinical benefit in non-small cell lung cancer (NSCLC) patients with EGFR-activating mutations. However, the potential therapeutic effects of afatinib combining with other...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467405/ https://www.ncbi.nlm.nih.gov/pubmed/25714021 |
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author | Zhang, Shirong Zheng, Xiaoliang Huang, Haixiu Wu, Kan Wang, Bing Chen, Xufeng Ma, Shenglin |
author_facet | Zhang, Shirong Zheng, Xiaoliang Huang, Haixiu Wu, Kan Wang, Bing Chen, Xufeng Ma, Shenglin |
author_sort | Zhang, Shirong |
collection | PubMed |
description | Afatinib is a second-generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and has shown a significant clinical benefit in non-small cell lung cancer (NSCLC) patients with EGFR-activating mutations. However, the potential therapeutic effects of afatinib combining with other modalities, including ionizing radiation (IR), are not well understood. In this study, we developed a gefitinib-resistant cell subline (PC-9-GR) with a secondary EGFR mutation (T790M) from NSCLC PC-9 cells after chronic exposures to increasing doses of gefitinib. The presence of afatinib significantly increases the cell killing effect of radiation in PC-9-GR cells harboring acquired T790M, but not in H1975 cells with de novo T790M or in H460 cells that express wild-type EGFR. In PC-9-GR cells, afatinib remarkable blocks baseline of EGFR and ERK phosphorylations, and causes delay of IR-induced AKT phosphorylation. Afatinib treatment also leads to increased apoptosis and suppressed DNA damage repair in irradiated PC-9-GR cells, and enhanced tumor growth inhibition when combined with IR in PC-9-GR xenografts. Our findings suggest a potential therapeutic impact of afatinib as a radiation sensitizer in lung cancer cells harboring acquired T790M mutation, providing a rationale for a clinical trial with combination of afatinib and radiation in NSCLCs with EGFR T790M mutation. |
format | Online Article Text |
id | pubmed-4467405 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-44674052015-06-22 Afatinib increases sensitivity to radiation in non-small cell lung cancer cells with acquired EGFR T790M mutation Zhang, Shirong Zheng, Xiaoliang Huang, Haixiu Wu, Kan Wang, Bing Chen, Xufeng Ma, Shenglin Oncotarget Research Paper Afatinib is a second-generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and has shown a significant clinical benefit in non-small cell lung cancer (NSCLC) patients with EGFR-activating mutations. However, the potential therapeutic effects of afatinib combining with other modalities, including ionizing radiation (IR), are not well understood. In this study, we developed a gefitinib-resistant cell subline (PC-9-GR) with a secondary EGFR mutation (T790M) from NSCLC PC-9 cells after chronic exposures to increasing doses of gefitinib. The presence of afatinib significantly increases the cell killing effect of radiation in PC-9-GR cells harboring acquired T790M, but not in H1975 cells with de novo T790M or in H460 cells that express wild-type EGFR. In PC-9-GR cells, afatinib remarkable blocks baseline of EGFR and ERK phosphorylations, and causes delay of IR-induced AKT phosphorylation. Afatinib treatment also leads to increased apoptosis and suppressed DNA damage repair in irradiated PC-9-GR cells, and enhanced tumor growth inhibition when combined with IR in PC-9-GR xenografts. Our findings suggest a potential therapeutic impact of afatinib as a radiation sensitizer in lung cancer cells harboring acquired T790M mutation, providing a rationale for a clinical trial with combination of afatinib and radiation in NSCLCs with EGFR T790M mutation. Impact Journals LLC 2015-01-21 /pmc/articles/PMC4467405/ /pubmed/25714021 Text en Copyright: © 2015 Zhang et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Zhang, Shirong Zheng, Xiaoliang Huang, Haixiu Wu, Kan Wang, Bing Chen, Xufeng Ma, Shenglin Afatinib increases sensitivity to radiation in non-small cell lung cancer cells with acquired EGFR T790M mutation |
title | Afatinib increases sensitivity to radiation in non-small cell lung cancer cells with acquired EGFR T790M mutation |
title_full | Afatinib increases sensitivity to radiation in non-small cell lung cancer cells with acquired EGFR T790M mutation |
title_fullStr | Afatinib increases sensitivity to radiation in non-small cell lung cancer cells with acquired EGFR T790M mutation |
title_full_unstemmed | Afatinib increases sensitivity to radiation in non-small cell lung cancer cells with acquired EGFR T790M mutation |
title_short | Afatinib increases sensitivity to radiation in non-small cell lung cancer cells with acquired EGFR T790M mutation |
title_sort | afatinib increases sensitivity to radiation in non-small cell lung cancer cells with acquired egfr t790m mutation |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467405/ https://www.ncbi.nlm.nih.gov/pubmed/25714021 |
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