Chemical genomics reveals inhibition of breast cancer lung metastasis by Ponatinib via c-Jun. Issue 3 (17th April 2018)

• Record Type: Journal Article
• Authors: Shao, Wei; Li, Shasha; Li, Lu; Lin, Kequan; Liu, Xinhong; Wang, Haiyan; Wang, Huili; Wang, Dong
• Is Part Of: Protein & cell. Volume 10:Issue 3(2019)
• Page Start: 161
• Page End: 177
• Publication Date: 2018-04-17
• Subjects: anti-metastatic drug discovery -- gene expression signature -- high-throughput sequencing-based high-throughput screening -- Ponatinib -- breast cancer lung metastasis -- c-Jun; Proteins -- Periodicals; Cells -- Periodicals; Cytology -- Periodicals; 572.6
• DOI: 10.1007/s13238-018-0533-8
• Languages: English
• ISSNs: 1674-800X

Abstract

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 2 ) 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.