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.
Highlights
The absence of effective and high-throughput metastatic cell models in vitro has obstructed anti-metastatic drug discovery
We determined that Ponatinib, a tyrosine-kinase inhibitor, represses breast cancer lung metastasis (BCLM)-associated gene expression via the extracellular-signal-regulated kinase (ERK)/c-Jun signaling pathway and inhibits BCLM in mouse models
By RT-qPCR, we confirmed that Ponatinib dose- and time- dependently affected the expression of 6 BCLM-associated genes, including angiopoietin-like 4 (ANGPTL4), matrix metalloproteinase-1 (MMP1), prostaglandin-endoperoxide synthase 2 (PTGS2), tenascin C (TNC), lymphocyte antigen 6e (LY6E) and retinoic acid receptor responder protein 3 (RARRES3) (Fig. 1F and 1G)
Summary
The absence of effective and high-throughput metastatic cell models in vitro has obstructed anti-metastatic drug discovery. Transwell migration or wound healing assays can be used to study cell migration or invasion; and softagar colony-formation assays are a well-established method for characterizing cell colonization capability. These assays cannot completely reflect the cancer metastatic process and are not suitable for anti-metastatic drug discovery. Despite enormous efforts in academia and industry to develop anti-metastasis medications for breast cancer, no drugs are available on the market. There is an urgent needed for effective medical treatments for breast cancer metastasis
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