Characterization of NRF2 expression and its pro- and anti-ferroptotic targets in Non-Small Cell Lung Cancer

• Grant number: 24/17773-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: December 01, 2024
• End date: November 30, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Clarissa Ribeiro Reily Rocha
• Grantee: Luísa Kawakami Piratello
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 19/19435-3 - The role of DNA damage and mitochondrial function in vascular, immune and neurological ageing (DNA MoVINg), AP.TEM

Abstract

NRF2 is a transcription factor that plays a central role in the cellular response to oxidative stress. Mutations in the KEAP1/NRF2 pathway are relatively common in lung cancer and are often associated with poor patient prognosis. This is due to resistance to major treatments, such as chemotherapy and immunotherapy, since antioxidant genes are induced, protecting tumor cells against cell death. Ferroptosis is a recently described type of programmed cell death characterized by intracellular iron accumulation and lipid peroxidation. Recently, this type of cell death has been explored as a possible alternative to therapeutic treatment for different tumor types. However, the NRF2 role in regulating ferroptosis is still unclear. In this project, we intend to analyze the impact of NRF2 activity on modulating ferroptosis in lung cancer cell lines. For this purpose, we will use lung cancer cell cultures with different levels of NRF2 expression. The hyperactivation of the NRF2/KEAP1 pathway in iron-dependent cell death will also be studied, investigating a possible NRF2-dependent control of ferroptosis in this tumor subtype. Thus, since patients resistant to conventional therapies still do not have an efficient and clinically validated therapeutic alternative, we believe that this project is highly justifiable and, more importantly, if successful, has the potential to contribute to the development of new therapies for lung cancer.