Potential Applications of NRF2 Inhibitors in Cancer Therapy

Figure 3

Mechanisms involved in the prooncogenic activation of the NRF2/KEAP1 pathway. Among the genetic alterations so far described, (a) somatic mutations located within specific domains of NRF2 and/or KEAP1 proteins can affect their reciprocal interaction or impair the negative control exerted by other regulators of NRF2 stability such as Rbx1 and Cul3. Also, (b) genetic deletion of NRF2 exon2 can be responsible for impaired NRF2-KEAP1 interaction. In all the cases, NRF2-dependent transcription is potentiated. As concerning the epigenetic changes, (a) either hypermethylation of the CpG islands in the KEAP1 promoter region, (b) the decreased methylation of the CpG islands within the NRF2 promoter, or (c) the inhibition of KEAP1 mRNA translation exerted by certain miRNAs can lead to NRF2 hyperactivation. Moreover, (d) enhanced NRF2 expression can also occur in response to upstream oncogenic signaling triggered by aberrant KRAS and BRAF activation. Also, (g) metabolic changes leading to succinate accumulation can promote KEAP1 succinylation and prevent its interaction with NRF2. Lastly, increased NRF2 nuclear translocation and transactivation can be induced by (h) PI3K-Akt-mediated inhibition of GSK3 or direct interaction with protein regulators such as (i) p21, (j) p62, and (k) dpp3.