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.