Mesenchymal-epithelial transition and AXL inhibitor TP-0903 sensitise triple-negative breast cancer cells to the antimalarial compound, artesunate

Triple-negative cancer of the breast (TNBC) is really a difficult-to-treat, aggressive cancer type. TNBC is frequently connected using the cellular program of epithelial-mesenchymal transition (EMT) that confers drug resistance and metastasis. EMT and reverse mesenchymal-epithelial transition (MET) programs are controlled by a number of signaling pathways which converge on several transcription factors, EMT- TFs. Therapy approaches could depend around the EMT reversal to sensitise mesenchymal tumours to compounds effective against epithelial cancers. Here, we reveal that the antimalarial ROS-generating compound artesunate (ART) exhibits greater cytotoxicity in epithelial than mesenchymal cancer of the breast cell lines. Ectopic expression of EMT-TF ZEB1 in epithelial or ZEB1 depletion in mesenchymal cells, correspondingly, reduced or elevated ART-generated ROS levels, DNA damage and apoptotic cell dying. In epithelial cells, ZEB1 enhanced expression of superoxide dismutase 2 (SOD2) and glutathione peroxidase 8 (GPX8) implicated in ROS scavenging. Although SOD2 or GPX8 levels were unaffected in mesenchymal cells as a result of ZEB1 depletion, stable ZEB1 knockdown enhanced total ROS. Receptor tyrosine kinase AXL keeps a mesenchymal phenotype and it is overexpressed in TNBC. The clinically-relevant AXL inhibitor TP-0903 caused MET and synergised with ART to create ROS, DNA damage and apoptosis in TNBC cells. TP-0903 reduced the expression of GPX8 and SOD2. Thus, TP-0903 and ZEB1 knockdown sensitised TNBC cells to ART, likely via different pathways. Synergistic interactions between TP-0903 and ART indicate that combination approaches involving these compounds might have therapeutic prospects for TNBC treatment.