Poster Presentation 36th Lorne Cancer Conference 2024

Exploring the role of NRF2 and ferroptosis in oesophageal cancer (#133)

Zoe Nguyen 1 2 , Kristin Brown 1 2 3 , Wayne Phillips 1 2 4 , Nicholas Clemons 1 2
  1. Sir Peter MacCallum Department of Oncology , The University of Melbourne , Parkville , Victoria , Australia
  2. Division of Cancer Research , Peter MacCallum Cancer Centre , Melbourne , 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

The overall 5-year survival rate for oesophageal cancer remains relatively dismal at <15%. This is mainly due to a lack of effective treatments which is in turn a result of a poor understanding of disease pathogenesis. Oesophageal cancer is amongst the cancer types with the highest expression of NRF2, the master regulator of the cellular antioxidant response. High expression of the NRF2 pathway has previously been associated with poor prognosis and resistance to chemo- and radiotherapy. Furthermore, many canonical NRF2 target genes are involved in the defence mechanism against a form of metabolically programmed cell death known as ferroptosis. Thus, we hypothesized that oesophageal cancer resistance to chemo- and radiotherapy could be at least partly driven by resistance to ferroptosis. This research aims to elucidate the role of NRF2 pathway in oesophageal cancer development and progression, and determine whether hyperactivation of this pathway is responsible for driving to resistance chemo- and radiotherapy. Surprisingly, alteration of NRF2 and its target genes’ expression, either by NRF2 overexpression or siRNA-mediated NRF2 knockdown, did not have any significant effects on oesophageal cancer cell line sensitivity to various chemotherapies. However, oesophageal cancer cell line sensitivity to ferroptotic inducers was influenced by the alteration of NRF2 expression- either by overexpression or siRNA-mediated knockdown. These results suggest that oesophageal cancer cells resistance to ferroptosis could be NRF2-mediated, however, resistance to ferroptosis is not contributing to driving the resistance to chemotherapy.