Role of the KEAP1-NRF2 Axis in Renal Cell Carcinoma

SIMPLE SUMMARY: Renal cancers are common types of tumors affecting humans. While many different genes have been found to be mutated and to drive the initiation and progression of these lethal cancers, a fine molecular understanding of the process is still lacking. One important pathway that emerges central in many different types of renal cancers is one called KEAP-NRF2. This axis is very important in normal kidneys as a defense against oxidative stress. Here, we summarize a large body of literature suggesting that this axis is exploited by tumor cells to escape control and to transform, and thus it could represent a good target for therapy. ABSTRACT: NRF2 is a transcription factor that coordinates the antioxidant response in many different tissues, ensuring cytoprotection from endogenous and exogenous stress stimuli. In the kidney, its function is essential in appropriate cellular response to oxidative stress, however its aberrant activation supports progression, metastasis, and resistance to therapies in renal cell carcinoma, similarly to what happens in other nonrenal cancers. While at the moment direct inhibitors of NRF2 are not available, understanding the molecular mechanisms that regulate its hyperactivation in specific tumor types is crucial as it may open new therapeutic perspectives. Here, we focus our attention on renal cell carcinoma, describing how NRF2 hyperactivation can contribute to tumor progression and chemoresistance. Furthermore, we highlight the mechanism whereby the many pathways that are generally altered in these tumors converge to dysregulation of the KEAP1-NRF2 axis.