The Role of NRF2 Pathway in Ferroptosis in Non-Small Cell Lung Cancer

• Grant number: 24/17832-3
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: June 01, 2025
• End date: May 31, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Clarissa Ribeiro Reily Rocha
• Grantee: Karoline Almeida Lima
• Supervisor: Jose Pedro Friedmann Angeli
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Institution abroad: Julius-Maximilians-Universität Würzburg (JMU), Germany
• Associated to the scholarship: 23/04387-9 - Role of NRF2 in the Process of cell death by ferroptosis in Non-Small Cell Lung Cancer, BP.DR

Abstract

Lung cancer is one of most prevalent and aggressive type of tumor, characterized by the highly molecular heterogenicity. Mutations in the KEAP1/NRF2 pathway occur in approximately 20-30% of non-small cell lung cancers (NSCLC). These mutations are associated with poor prognosis and resistance to chemotherapy and immunotherapy due to their ability to induce antioxidant genes expression and, consequently, protect tumor cells from death. Ferroptosis, a recently discovered form of programmed cell death, dependent on iron and characterized by the accumulation of lipid peroxides, has emerged as a potential therapeutic alternative in cancer. Additionally, recent research suggests that ferroptosis may contribute to the antitumor efficacy of anti-PDL1 immunotherapy. However, the role of NRF2 in regulating ferroptosis upon immunotherapy remains not fully elucidated. Thus, given the high frequency of NRF2 pathway mutations in lung cancer and its potential role in ferroptosis regulation, this BEPE project aims to investigate the role of NRF2 and its target genes, FSP1 and SLC7A11, in modulating ferroptosis in NSCLC cell lines treated with interferon gamma (IFN-¿). For this purpose, we will use a CRISPR to knockout FSP1 or SLC7A11 in a NSCLC cell lines, and treat with ferroptosis inducer in combination with IFN-¿. Finally, we will also investigate the molecular mechanisms linking PDL1 to ferroptosis and NRF2 activity. We believe that this project will be important for future clinical trials seeking therapeutic alternatives for this molecular subtype of lung cancer, which remains resistant and lacks validated targeted therapies, making it an extremely challenging disease.