Exploring the role of NRF2 as mediator of tumor resistance to chemotherapy

Abstract

Different types of cancer figure among the leading causes of morbidity, and mortality worldwide. The main factor for cancer treatment failure is antitumoral therapy resistance. Several mechanisms command drug resistance and many of those can be tissue or drug-specific (or both). As different pathways might contribute to tumor chemoresistance in different proportions, it is fundamental to identify the key molecular regulator of those resistance factors. In order to achieve a better therapeutic efficacy, it is paramount to eliminate drug resistance. Glioma and melanoma are particularly aggressive and severe types of tumor. Temozolomide (TMZ) and cisplatin are among the most used chemicals to treat glioma and metastatic melanoma. However, chemotherapy has limited success on those patients, and as a consequence those types of tumor remain incurable. In this proposal, we plan to investigate the TMZ and cisplatin resistance mechanisms' mediators on both glioma and melanoma cell lines. We hypothesize that the antioxidant transcriptional factor NRF2 may be central mediators for TMZ and cisplatin resistance. In this project, we aim to generate NRF2 knockout (NRF2-KO) and NRF2 constitutively activated (NRF2-Act) cell lines, using the CRISPR/Cas9 genome editing system. On those cells, we are going to evaluate, both in vitro and in vivo models, important drug resistance mechanisms such as DNA repair capacity, glutathione intracellular level and apoptosis induction upon TMZ and cisplatin treatment. These cutting edge molecular tools and unique in vivo models developed at Prof. Samson and Prof. Engelward laboratory at Massachusetts Institute of Technology (MIT), which will help us to evaluate how NRF2 mediated pathway affects DNA repair pathways. Ultimately, as consequence of success of this proposal, we intent to design and implement more adequate and efficient protocols for clinical application to treat glioma and melanoma patients, aiming at improved chemotherapeutic efficacy and less adverse side effects. Thus, we hope this proposal will contribute to improve our knowledge concerning drug resistance in glioma and melanoma cells what, in turn, will fundament future clinical trials to treat those patients. (AU)