NRF2 activation induces NADH-reductive stress, providing a metabolic vulnerability in lung cancer

• DOI: 10.1016/j.cmet.2023.01.012
• Publication Date: 2023-02-24T15:49:49Z
• Authors: Tommy Weiss-Sadan; Maolin Ge; Makiko Hayashi; Magdy Gohar; Cong-Hui Yao; Adriaan de Groot; Stefan Harry; Alexander Carlin; Hannah Fischer; Lei Shi; Ting-Yu Wei; Charles H. Adelmann; Konstantin Wolf; Tristan Vornbäumen; Benedikt R. Dürr; Mariko Takahashi; Marianne Richter; Junbing Zhang; Tzu-Yi Yang; Vindhya Vijay; David E. Fisher; Aaron N. Hata; Marcia C. Haigis; Raul Mostoslavsky; Nabeel Bardeesy; Thales Papagianna...; Liron Bar-Peled
• Keywords: Kelch-Like ECH-Associated Protein 1; Lung Neoplasms; NF-E2-Related Factor 2; NAD; 3. Good health; Oxidative Stress; 03 medical and health sciences; 0302 clinical medicine; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Humans; Signal Transduction

Multiple cancers regulate oxidative stress by activating the transcription factor NRF2 through mutation of its negative regulator, KEAP1. NRF2 has been studied extensively in KEAP1-mutant cancers; however, the role of this pathway in cancers with wild-type KEAP1 remains poorly understood. To answer this question, we induced NRF2 via pharmacological inactivation of KEAP1 in a panel of 50+ non-small cell lung cancer cell lines. Unexpectedly, marked decreases in viability were observed in >13% of the cell lines-an effect that was rescued by NRF2 ablation. Genome-wide and targeted CRISPR screens revealed that NRF2 induces NADH-reductive stress, through the upregulation of the NAD+-consuming enzyme ALDH3A1. Leveraging these findings, we show that cells treated with KEAP1 inhibitors or those with endogenous KEAP1 mutations are selectively vulnerable to Complex I inhibition, which impairs NADH oxidation capacity and potentiates reductive stress. Thus, we identify reductive stress as a metabolic vulnerability in NRF2-activated lung cancers.