NRF2 addiction in cancer cells

The Kelch‐like ECH ‐associated protein 1/nuclear factor erythroid‐derived 2‐like 2 ( KEAP 1‐ NRF 2) system is a pivotal defense mechanism against oxidative and electrophilic stress. Although transient NRF 2 activation in response to stress is beneficial for health, persistent NRF 2 activation in cancer cells has deleterious effects on cancer‐bearing hosts by conferring therapeutic resistance and aggressive tumorigenic activity on cancer cells. Because NRF 2 increases the antioxidant and detoxification capability of cancer cells, persistently high levels of NRF 2 activity enhance therapeutic resistance of cancer cells. NRF 2 also drives metabolic reprogramming to establish cellular metabolic processes that are advantageous for cell proliferation in cooperation with other oncogenic pathways. As a result of these advantages, cancer cells with persistent activation of NRF 2 often develop “ NRF 2 addiction” and show malignant phenotypes leading to poor prognoses in cancer patients. Inhibition of NRF 2 is a promising therapeutic approach for NRF 2‐addicted cancers and NRF 2 inhibitors are being actively developed. However, giving systemic NRF 2 inhibitors might have undesirable effects on cancer‐bearing hosts, considering the central roles of NRF 2 in cytoprotection. To avoid these side‐effects, new therapeutic targets besides NRF 2 for NRF 2‐addicted cancers have been actively explored. This review introduces recent studies describing the development and characterization of NRF 2‐addicted cancers, as well as their potential therapeutic targets. Expected advances in diagnostic and therapeutic interventions for NRF 2‐addicted cancers are also discussed.