title: Afatinib increases sensitivity to radiation in non-small cell lung cancer cells with acquired EGFR T790M mutation.
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.
authors.affiliation: Department of Radiation Oncology, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, Zhejiang, China.
authors.forename: Shirong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Centre of Molecular Medicine, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang, China.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Radiation Oncology, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, Zhejiang, China.
authors.forename: Haixiu
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Radiation Oncology, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, Zhejiang, China.
authors.forename: Kan
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Radiation Oncology, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, Zhejiang, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
authors.forename: Xufeng
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, Zhejiang, China.
authors.forename: Shenglin
authors.initials: S
authors.lastname: Ma
mesh_terms: D000077716:Afatinib; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D011799:Quinazolines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D000077716:Afatinib; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: EGFR; NSCLC; T790M; afatinib; radiosensitization