Reductive stress could be a chink in the armor of some lung cancers
To deal with oxidative stress, many cancers activate a regulator of gene expression, NRF2, by mutating the gene for its suppressor KEAP1. Although the molecular biology of such cancers has been extensively studied, less is known about those in which KEAP1 is not mutated. A study published in Cell Metabolism in February led by Ludwig Harvard’s Liron Bar-Peled—and co-authored by Harvard Center colleagues Marcia Haigis and Aaron Hata—induced NRF2 activation by pharmacologically inactivating KEAP1 in a panel of more than 50 non-small cell lung cancer cell lines. The researchers found, surprisingly, that about 13% of the cell lines failed to survive when KEAP1 was inhibited, and that their viability could be restored by the ablation of NRF2. Examining this phenomenon, they discovered that NRF2 induces reductive stress in these cells by driving the production of ALDH3A1—an enzyme that consumes NAD+—causing an accumulation of the electron carrier NADH. Liron and his colleagues examined whether the buildup of electrons, or NADH-reductive stress, in these cells might be exploited to target cancers in which NRF2 is activated. They showed that such cancers are specifically vulnerable to inhibition of a core metabolic enzyme known as Complex 1 when their KEAP1 protein is inactivated pharmacologically or by genetic manipulation. Complex 1 inhibition boosts reductive stress by compromising NADH oxidation in these cancer cells, suggesting that reductive stress is a metabolic vulnerability of NRF2-activated cancers.