Shasha Li
Lu Li
Kequan Lin
Xinhong Liu
Haiyan Wang
Huili Wang
Dong Wang
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: 2018-02-06
Abstract
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.Keywords: anti-metastatic drug discovery,
gene expression signature,
high-throughput sequencing-based high-throughput screening,
Ponatinib,
breast cancer lung metastasis,
c-Jun
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