NRF2 addiction in cancer cells

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