Role of the KEAP1-NRF2 Axis in Renal Cell Carcinoma

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.

Integrative Clinical and Molecular Characterization of Translocation Renal Cell Carcinoma

“…4c), suggesting a direct link between MiT/TFE fusions and the NRF2 pathway in tRCC. Our results may explain why tRCCs (and ccRCCs with elevated NRF2 signaling) display worse outcomes with sunitinib than with ICI in clinical datasets, and are consistent with in vitro data suggesting that NRF2 confers resistance to sunitinib and other TKIs 55,86,87 . Whether this signal holds for extended spectrum kinase inhibitors such as cabozantinib and lenvatinib remains to be determined, as patients receiving these therapies were not represented in our retrospective cohort.…”

“…The transcription factor NRF2 (nuclear factor erythroid-derived-2-like 2, NFE2L2) is a master regulator of the cellular antioxidant response and controls the expression of genes involved in the response to xenobiotics and oxidative stress 54 . Notably, activation of the NRF2 pathway has been reported in certain subsets of RCC via diverse mechanisms that include somatic alteration or hypermethylation of NRF2 pathway members 55 and the production of oncometabolites that modify and inhibit KEAP1, a negative regulator of NRF2 7,10,27 . Given evidence of activated ROS-sensing in tRCC (Fig.…”

Immune Checkpoint Inhibition in Advanced Non-Clear Cell Renal Cell Carcinoma: Leveraging Success from Clear Cell Histology into New Opportunities

“…NRF2 is a key transcription factor that activates the endogenous antioxidant response by regulating cellular antioxidant stress [44]. Mutated NRF2 was initially related to type II papillary RCC but is now recognized as a common feature among many RCC types [45]. Aberrant NRF2 activation is as a central driver of progression and is associated with a decreased survival [37].…”

“…FH is an enzyme of the tricarboxylic acid cycle, and aberrant activity leads to an intracellular accumulation of fumarate, which acts as an oncometabolite. In addition, fumarate is responsible for the stabilization of both HIF-1α and NRF2 [45]. The discovery that a loss of FH leads to HIF-1α overexpression is hypothesis-generating and suggests a potential antitumor activity from HIF-1α inhibitors in non-clear cell RCC with FH mutations [48].…”

External Validation of the Prognostic Value of an Immune-Associated Gene Panel for Clear Cell Renal Cell Carcinomas

“…Presently, surgery is the main treatment for ccRCC, but this is correlated with a high incidence of recurrence and metastasis ( Sorokin et al, 2017 ). Furthermore, ccRCCs are radioresistant ( Bielecka et al, 2014 ), and more than 80% are chemoresistant ( Clerici and Boletta, 2020 ), with agents producing a positive response only in a minority of patients. Since ccRCCs are presumed to be immunogenic ( Xu et al, 2020 ), immunotherapy has been widely employed and shows promising clinical effects in the treatment of renal cancer.…”