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

  • Protein Cell. 2019 Mar;10(3):161-177. doi: 10.1007/s13238-018-0533-8.
Wei Shao  1 ,  Shasha Li  1 ,  Lu Li  1 ,  Kequan Lin  1 ,  Xinhong Liu  1 ,  Haiyan Wang  1 ,  Huili Wang  1 ,  Dong Wang  2  3  4
Affiliations
  • 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. [email protected].
  • 3. Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Sichuan, 610041, China. [email protected].
  • 4. Center for Synthetic and Systems Biology, Tsinghua University, Beijing, 100084, China. [email protected].
PMID: 29667003 DOI: 10.1007/s13238-018-0533-8
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 (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
Ponatinib; anti-metastatic drug discovery; breast cancer lung metastasis; c-Jun; gene expression signature; high-throughput sequencing-based high-throughput screening.
Products