The role of autophagy and NRF2 pathways in ferroptosis

Abstract

Cancer is a leading cause of death worldwide, and while great advances have been made particularly in chemotherapy, many types of cancer still present a dismal prognosis. Glioma is the most common primary cancer of the central nervous system, and around half of the patients present with the most aggressive form of the disease, glioblastoma. The alkylating agent temozolomide (TMZ) is the first-line drug to treat glioblastoma patients, however this drug has limited success due to drug resistance. While several TMZ resistance mechanisms have been described, it has been speculated that many more remain to be uncovered. Hence, to develop glioblastoma therapies of clinical relevance, it is imperative to better understand TMZ resistance and discover novel synthetic lethal partners for TMZ combination therapies preventing tumor recurrence. In previous works our group demonstrated that the transcription factor NRF2 plays a fundamental role on TMZ resistance. Interestingly, NRF2 modulates several cellular pathways such as macroautophagy and chaperone mediated autophagy (CMA). In addition, NRF2 is also involved in a novel regulated cell death named ferroptosis. Thus, in order to obtain a substantial improvement on glioblastoma efficacy treatment, this proposal focus in 2 sub-projects: analysis of the role NRF2 on ferroptosis and TMZ resistance; and explore the crosstalk between macroautophagy and CMA on ferroptosis modulation. There is an urgent medical need for therapeutic alternatives to treat glioblastoma patients. If successful, this project will identify novel combination therapy leads to pursue in the clinic with TMZ. We strongly believe that the knowledge obtained from the proposed work will help design more adequate and efficient chemotherapy strategies to treat glioblastoma patients. (AU)