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

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

  • Sci Rep. 2024 Jan 3;14(1):425. doi: 10.1038/s41598-023-50710-3.
Mirko Terragno 1 Anastassiya Vetrova 2 Oleg Semenov 3 A Emre Sayan 4 Marina Kriajevska 2 5 Eugene Tulchinsky 6 7
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana, Kazakhstan. mirko.terragno@nu.edu.kz.
  • 2 Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana, Kazakhstan.
  • 3 Regulation of Gene Expression Laboratory, Institute of Cytology RAS, Saint Petersburg, Russia.
  • 4 Cancer Sciences Division, University of Southampton, Southampton, UK.
  • 5 Department of Genetics and Genome Biology, University of Leicester, Leicester, UK.
  • 6 Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana, Kazakhstan. eugene.tulchinsky@nu.edu.kz.
  • 7 Department of Genetics and Genome Biology, University of Leicester, Leicester, UK. eugene.tulchinsky@nu.edu.kz.
Abstract

Triple-negative breast Cancer (TNBC) is a difficult-to-treat, aggressive Cancer type. TNBC is often associated with the cellular program of epithelial-mesenchymal transition (EMT) that confers drug resistance and metastasis. EMT and reverse mesenchymal-epithelial transition (MET) programs are regulated by several signaling pathways which converge on a group of transcription factors, EMT- TFs. Therapy approaches could rely on the EMT reversal to sensitise mesenchymal tumours to compounds effective against epithelial cancers. Here, we show that the antimalarial ROS-generating compound artesunate (ART) exhibits higher cytotoxicity in epithelial than mesenchymal breast Cancer cell lines. Ectopic expression of EMT-TF ZEB1 in epithelial or ZEB1 depletion in mesenchymal cells, respectively, reduced or increased ART-generated ROS levels, DNA damage and apoptotic cell death. 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 in response to ZEB1 depletion, stable ZEB1 knockdown enhanced total ROS. Receptor tyrosine kinase AXL maintains a mesenchymal phenotype and is overexpressed in TNBC. The clinically-relevant Axl Inhibitor TP-0903 induced MET and synergised with ART to generate 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 can have therapeutic prospects for TNBC treatment.

Figures
Products