RESEARCH ARTICLE

Chemical genomics reveals inhibition of breast cancer lung metastasis by Ponatinib via c-Jun

  • Wei Shao 1 ,
  • Shasha Li 1 ,
  • Lu Li 1 ,
  • Kequan Lin 1 ,
  • Xinhong Liu 1 ,
  • Haiyan Wang 1 ,
  • Huili Wang 1 ,
  • Dong Wang , 1,2,3
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  • 1. Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
  • 2. Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China
  • 3. Center for Synthetic and Systems Biology, Tsinghua University, Beijing 100084, China

Received date: 06 Feb 2018

Accepted date: 14 Mar 2018

Published date: 21 Feb 2019

Copyright

2018 The Author(s) 2018

Abstract

Metastasis is the leading cause of human cancer deaths. Unfortunately, no approved drugs are available for antimetastatic treatment. In our study, high-throughput sequencing-based high-throughput screening (HTS2) and a breast cancer lung metastasis (BCLM)-associated gene signature were combined to discover anti-metastatic drugs. After screening of thousands of compounds, we identified Ponatinib as a BCLM inhibitor. Ponatinib significantly inhibited the migration and mammosphere formation of breast cancer cells in vitro and blocked BCLM in multiple mouse models. Mechanistically, Ponatinib represses the expression of BCLM-associated genes mainly through the ERK/c-Jun signaling pathway by inhibiting the transcription of JUN and accelerating the degradation of c-Jun protein. Notably, JUN expression levels were positively correlated with BCLM-associated gene expression and lung metastases in breast cancer patients. Collectively, we established a novel approach for the discovery of anti-metastatic drugs, identified Ponatinib as a new drug to inhibit BCLM and revealed c-Jun as a crucial factor and potential drug target for BCLM. Our study may facilitate the therapeutic treatment of BCLM as well as other metastases.

Cite this article

Wei Shao , Shasha Li , Lu Li , Kequan Lin , Xinhong Liu , Haiyan Wang , Huili Wang , Dong Wang . Chemical genomics reveals inhibition of breast cancer lung metastasis by Ponatinib via c-Jun[J]. Protein & Cell, 2019 , 10(3) : 161 -177 . DOI: 10.1007/s13238-018-0533-8

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