Chemical genomics reveals inhibition of breast cancer lung metastasis by Ponatinib via c-Jun.
10.1007/s13238-018-0533-8
- Author:
Wei SHAO
1
;
Shasha LI
1
;
Lu LI
1
;
Kequan LIN
1
;
Xinhong LIU
1
;
Haiyan WANG
1
;
Huili WANG
1
;
Dong WANG
2
Author Information
1. Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, China.
2. Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, China. dwang@biomed.tsinghua.edu.cn.
- Publication Type:Journal Article
- Keywords:
Ponatinib;
anti-metastatic drug discovery;
breast cancer lung metastasis;
c-Jun;
gene expression signature;
high-throughput sequencing-based high-throughput screening
- From:
Protein & Cell
2019;10(3):161-177
- CountryChina
- Language:English
-
Abstract:
Metastasis is the leading cause of human cancer deaths. Unfortunately, no approved drugs are available for anti-metastatic treatment. In our study, high-throughput sequencing-based high-throughput screening (HTS) 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.
