Oncotarget

Research Papers:

Afatinib increases sensitivity to radiation in non-small cell lung cancer cells with acquired EGFR T790M mutation

Shirong Zhang, Xiaoliang Zheng, Haixiu Huang, Kan Wu, Bing Wang, Xufeng Chen and Shenglin Ma _

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Oncotarget. 2015; 6:5832-5845. https://doi.org/10.18632/oncotarget.3332

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Abstract

Shirong Zhang1,*, Xiaoliang Zheng2,*, Haixiu Huang1, Kan Wu1, Bing Wang1, Xufeng Chen3 and Shenglin Ma1

1 Department of Radiation Oncology, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, Zhejiang, China

2 Centre of Molecular Medicine, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang, China

3 Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, CA, USA

* These authors co-contribute to this article

Correspondence:

Shenglin Ma, email:

Xufeng Chen, email:

Keywords: afatinib, radiosensitization, NSCLC, EGFR, T790M

Received: August 27, 2014 Accepted: January 03, 2015 Published: January 21, 2015

Abstract

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.


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