Role of NRF2 in the Process of cell death by ferroptosis in Non-Small Cell Lung Cancer

• Grant number: 23/04387-9
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: August 01, 2023
• Status: Discontinued
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Clarissa Ribeiro Reily Rocha
• Grantee: Karoline Almeida Lima
• 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
• Associated scholarship(s): 24/17832-3 - The Role of NRF2 Pathway in Ferroptosis in Non-Small Cell Lung Cancer, BE.EP.DR

Abstract

Approximately 20-30% of non-small cell lung cancers (NSCLC) have mutations in the NRF2 pathway. Due to their ability to induce the expression of antioxidant genes and protect the tumor cell from cell death, these mutations have been associated with a poor prognosis and resistance to chemotherapy and immunotherapies. Ferroptosis is a recently discovered type of programmed cell death, which has been explored as an alternative therapy in cancer, where ferroptosis inducers have been shown to be efficient in clinical studies in different tumor types. Recent literature suggests that ferroptosis contributes to the antitumor efficacy of antiPDL1 immunotherapy. However, the role of the transcription factor NRF2 in the regulation of ferroptosis still needs to be clarified. Due to the high occurrence of mutations in the NRF2 pathway in lung cancer, and its potential role in the regulation of ferroptosis, in this project we seek to elucidate the role of NRF2 and its target genes in the modulation of ferroptosis in NSCLC cell lines, in order to understand whether these cells can be resensitized to chemotherapy and immunotherapeutic treatments in combination with induction of ferroptosis and modulation of NRF2. For this, we will use NSCLC cell lines with different NRF2 expression patterns to determine their sensitivity to ferroptosis. As well as, we will characterize the expression of NRF2 and its anti and pro-ferroptotic target genes in lung adenocarcinoma cell lines. Also, we will analyze the effects of hyperactivation of the KEAP1/NRF2 pathway on iron-dependent cell death, investigating a possible NRF2-dependent control of ferroptosis in this tumor subtype. Validating NRF2-regulated ferroptotic genes and correlating transcription factor expression with ferroptosis signature. And, finally, we will evaluate a possible synergy in the treatment with ferroptosis modulators and chemotherapy and/or immunotherapeutics of NSCLC cell lines with different levels of NRF2 expression, as well as investigating the molecular mechanisms that link PDL1 to ferroptosis. We believe that the results of this project have great potential to serve as a basis for future clinical trials in the search for therapeutic alternatives for this molecular subtype of resistant lung cancer and without a clinically validated target therapy, proving to be an extremely challenging disease. (AU)