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Establishment of a Conditional Transgenic Mouse Model Recapitulating EML4-ALK-Positive Human Non-Small Cell Lung Cancer

 Kyoung Ho Pyo  ;  Sun Min Lim  ;  Hye Ryun Kim  ;  Young Hoon Sung  ;  Mi Ran Yun  ;  Sung-Moo Kim  ;  Hwan Kim  ;  Han Na Kang  ;  Ji Min Lee  ;  Sang Gyun Kim  ;  Chae Won Park  ;  Hyun Chang  ;  Hyo Sup Shim  ;  Han-Woong Lee  ;  Byoung Chul Cho 
 JOURNAL OF THORACIC ONCOLOGY, Vol.12(3) : 491-500, 2017 
Journal Title
Issue Date
Animals ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/pathology* ; Disease Models, Animal* ; Female ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology* ; Male ; Mice ; Mice, Transgenic ; Oncogene Proteins, Fusion/genetics* ; Oncogene Proteins, Fusion/metabolism ; Protein Kinase Inhibitors/therapeutic use* ; Tumor Cells, Cultured
Cre-LoxP ; EML4-ALK ; Lung cancer ; SPC promoter ; Transgenic mouse
BACKGROUND: Anaplastic lymphoma receptor tyrosine kinase gene (ALK) fusion is a distinct molecular subclassification of NSCLC that is targeted by anaplastic lymphoma kinase (ALK) inhibitors. We established a transgenic mouse model that expresses tumors highly resembling human NSCLC harboring echinoderm microtubule associated protein like 4 gene (EML)-ALK fusion. We aimed to test an EML4-ALK transgenic mouse model as a platform for assessing the efficacy of ALK inhibitors and examining mechanisms of acquired resistance to ALK inhibitors.

METHODS: Transgenic mouse lines harboring LoxP-STOP-LoxP-FLAGS-tagged human EML4-ALK (variant 1) transgene was established by using C57BL/6N mice. The transgenic mouse model with highly lung-specific, inducible expression of echinoderm microtubule associated protein like 4-ALK fusion protein was established by crossing the EML4-ALK transgenic mice with mice expressing Cre-estrogen receptor fusion protein under the control of surfactant protein C gene (SPC). Expression of EML4-ALK transgene was induced by intraperitoneally injecting mice with tamoxifen. When the lung tumor of the mice treated with the ALK inhibitor crizotinib for 2 weeks was measured, tumor shrinkage was observed.

RESULTS: EML4-ALK tumor developed after 1 week of tamoxifen treatment. Echinoderm microtubule associated protein like 4-ALK was strongly expressed in the lung but not in other organs. ALK and FLAGS expressions were observed by immunohistochemistry. Treatment of EML4-ALK tumor-bearing mice with crizotinib for 2 weeks induced dramatic shrinkage of tumors with no signs of toxicity. Furthermore, prolonged treatment with crizotinib led to acquired resistance in tumors, resulting in regrowth and disease progression. The resistant tumor nodules revealed acquired ALK G1202R mutations.

CONCLUSIONS: An EML4-ALK transgenic mouse model for study of drug resistance was successfully established with short duration of tumorigenesis. This model should be a strong preclinical model for testing efficacy of ALK TKIs, providing a useful tool for investigating the mechanisms of acquired resistance and pursuing novel treatment strategies in ALK-positive lung cancer.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kang, Han Na(강한나)
Kim, Sang Gyun(김상균)
Kim, Sung Moo(김성무)
Kim, Hye Ryun(김혜련) ORCID logo https://orcid.org/0000-0002-1842-9070
Kim, Hwan(김환)
Yun, Mi Ran(윤미란)
Lim, Sun Min(임선민)
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
Pyo, Kyoung Ho(표경호) ORCID logo https://orcid.org/0000-0001-5428-0288
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