NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism

The survival and recurrence of dormant tumour cells following therapy is a leading cause of death in patients with cancer. The metabolic properties of these cells are likely to be distinct from those of rapidly growing tumours. Here we show that Her2 downregulation in breast cancer cells promotes changes in cellular metabolism, culminating in oxidative stress and compensatory upregulation of the antioxidant transcription factor NRF2. NRF2 is activated during dormancy and in recurrent tumours in animal models and patients with breast cancer with poor prognosis. Constitutive activation of NRF2 accelerates recurrence, whereas suppression of NRF2 impairs it. In recurrent tumours, NRF2 signalling induces a transcriptional metabolic reprogramming to re-establish redox homeostasis and upregulate de novo nucleotide synthesis. The NRF2-driven metabolic state renders recurrent tumour cells sensitive to glutaminase inhibition, which prevents reactivation of dormant tumour cells in vitro, suggesting that NRF2-high dormant and recurrent tumours may be targeted. These data provide evidence that NRF2-driven metabolic reprogramming promotes the recurrence of dormant breast cancer.