From Harris and DeNicola, Trends in Cell Biology 2020

    

Understanding the complex roles of NRF2 in tumor progression and metastasis

NRF2 is a stress-responsive transcription factor that directs select transcriptional programs in response to oxidative stimuli. NRF2 levels are tightly controlled by KEAP1, which directs NRF2 destruction. Our early work demonstrated a critical role for K-Ras induced NRF2 transcription in lung and pancreatic tumor initiation (DeNicola et al. Nature 2011). Further, NRF2 and KEAP1 mutations are common in certain cancers, including non-small cell lung cancer, and lead to loss of NRF2 degradation and constitutive NRF2 accumulation, thereby promoting glutathione synthesis, detoxification of reactive oxygen species (ROS) and proliferation. In addition, we find NRF2 promotes resistance to ROS-generating therapy through the thioredoxin system, which can be reversed by targeting thioredoxin reductase or superoxide dismutase 1 (Torrente et al., Redox Biology 2020).

However, we find that the effects of NRF2 on tumor phenotypes are complex and highly context dependent. In a collaborative study with the Vousden lab, we showed that active suppression of ROS by NRF2 suppresses pancreatic cancer metastasis (Cheung et al., Cancer Cell 2020). To assess the effects of NRF2 activation on cellular metabolism and tumorigenesis in an isogenic system, we generated genetically engineered mouse models of both the NRF2D29H and KEAP1R554Q mutations found in human NSCLC. Surprisingly, these mouse models demonstrated that NRF2 activation impairs the progression of p53-deficient lung tumors (Kang et al. eLife 2019).

 

Open Questions:

  • Which specific antioxidant targets represent vulnerabilities for NRF2/KEAP1 mutant lung tumors?
  • Can we find druggable regulators of NRF2 in cells with KEAP1 loss of function?
  • Why does NRF2 activation impair progression of p53-deficient lung tumors?