Can’t KEEP Up: UXS1 Dependency Exposes a Pyrimidine Vulnerability in <i>KEAP1</i> -Mutant Lung Cancer

Loss-of-function mutations in KEAP1 are found in more than 20% of non-small cell lung cancers. These mutations stabilize the transcription factor NRF2 to induce a battery of antioxidative and cytoprotective genes. Although NRF2 accumulation promotes cancer cell fitness, it also creates several targetable vulnerabilities. In this issue of Cancer Research, Gebru and colleagues reveal the dependency of KEAP1-mutant non-small cell lung cancers on UDP-xylose synthase 1 (UXS1). The authors found that NRF2-driven expression of UDP-glucose 6-dehydrogenase leads to the accumulation of UDP-glucuronic acid. Consequently, loss of UXS1-mediated UDP-glucuronic acid decarboxylation causes sequestration of UDP, depletion of pyrimidine pools, and replication stress, thereby inducing apoptosis and senescence. Importantly, these effects are selective to KEAP1-mutant tumors, with KEAP1 wild-type cells and normal tissue unaffected by UXS1 loss. DNA damage induction with cell-cycle kinase inhibitors synergized with UXS1 loss to promote the death of KEAP1-mutant cells. These findings suggest that UXS1 loss is synthetic lethal with NRF2 activation and may be a promising target for therapy. See related article by Gebru et al., p. 4806.