Poster Presentation 35th Lorne Cancer Conference 2023

Exploiting vulnerabilities to ferroptosis to treat metastatic oesophageal cancer  (#264)

Zoe Nguyen 1 2 , David Liu 1 2 , Kristin Brown 1 2 3 , Wayne Phillips 1 2 4 , Nicholas Clemons 1 2
  1. Division of Cancer Research , Peter MacCallum Cancer Centre , Melbourne , Victoria , Australia
  2. Sir Peter MacCallum Department of Oncology , The University of Melbourne , Parkville , Victoria , Australia
  3. Department of Biochemistry and Pharmacology , The University of Melbourne , Parkville , Victoria , Australia
  4. Department of Surgery (St.Vincent's Hospital) , The University of Melbourne , Parkville , Victoria, Australia

Oesophageal cancer (OC) is amongst those cancers with the poorest prognosis, with a typical 5-year survival rate of <15%(1). This is largely attributable to resistance to first-line chemotherapies and the lack of effective treatments for advanced metastatic disease(2). Whilst most traditional chemotherapies induce cell death via apoptosis, alternative mechanisms of cell death also occur in cancer cells. Ferroptosis is an iron-dependent form of cell death induced by peroxidation of lipids, such as polyunsaturated fatty acids (PUFAs)(3).  A major defence mechanism against ferroptosis is the antioxidant response mediated by glutathione peroxidase (GPX4). GPX4 uses a key antioxidant, glutathione (GSH), to prevent accumulation of lethal lipid peroxides and subsequent ferroptotic cell death(4). Intriguingly, a mesenchymal cell state is often associated with acquired resistance to conventional therapies, and mesenchymal cells are highly dependent on GPX4 to protect against ferroptosis. This dependency is associated with the accumulation of PUFAs in the plasma membranes that occurs in mesenchymal cells(5). Compellingly, we have shown that FLO-1 OC cells that metastasise to the liver (FLO-1LM) express elevated levels of mesenchymal markers and are resistant to apoptosis induced by cisplatin(6). We have also shown that these metastatic cells are more sensitive to ferroptosis-inducing compounds than their parental counterparts. Thus, this study aims to investigate the vulnerability of metastatic OC cells to ferroptosis. This work will provide insight into how ferroptosis can be utilised to overcome resistance to traditional chemotherapies in OC.

 

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