Investigating the Conditional NRF2 Regulatory Network in Cancer (360G-Wellcome-109308_Z_15_A)

Dysregulation of the transcription factor nuclear factor-erythroid 2 p45-related factor 2 (NRF2) has been observed in many malignancies, and has been linked to both chemo and radio resistance. While the fundamental aspects of NRF2 regulation are relatively well-established, the mechanisms whereby NRF2 target genes are conditionally expressed under basal, de-repressed, or pathological conditions remain unclear. This severely limits the development of effective therapeutic strategies that target the NRF2 pathway. Therefore, this project aims to define conditional NRF2 target gene profiles and investigate the driving mechanisms behind the differential regulation of these genes. Initially a bioinformatics approach will be used to investigate differential NRF2 target gene profiles in a range of cancer-derived cell lines with non-physiological levels of NRF2. Subsequently, a subset of the cancer-derived cell lines identified from the bioinformatics screen will be subject to genetic manipulation to generate models of basal or de-repressed NRF2. Finally, comparative omic profiling of these models will be performed to identify the regulatory networks that give rise to differential expression of these NRF2 target genes. This data will be correlated with comparative proliferation and drug sensitivity profiles to provide new insight into pathophysiological mechanisms that drive cancers progression and drug resistance.