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

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6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)491-500
Number of pages10
JournalJournal of Thoracic Oncology
Volume12
Issue number3
DOIs
Publication statusPublished - 2017 Mar 1

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine

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    Pyo, K. H., Lim, S. M., Kim, H. R., Sung, Y. H., Yun, M. R., Kim, S. M., Kim, H., Kang, H. N., Lee, J. M., Kim, S. G., Park, C. W., Chang, H., Shim, H. S., Lee, H. W., & Cho, B. C. (2017). Establishment of a Conditional Transgenic Mouse Model Recapitulating EML4-ALK–Positive Human Non–Small Cell Lung Cancer. Journal of Thoracic Oncology, 12(3), 491-500. https://doi.org/10.1016/j.jtho.2016.10.022