Weiss-Sadan T, Ge M, Hayashi M, Gohar M, Yao CH, de Groot A, Harry S, Carlin A, Fischer H, Shi L, Wei TY, Adelmann CH, Wolf K, Vornbäumen T, Dürr BR, Takahashi M, Richter M, Zhang J, Yang TY, Vijay V, Fisher DE, Hata AN, Haigis MC, Mostoslavsky R, Bardeesy N, Papagiannakopoulos T, and Bar-Peled L
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., Competing Interests: Declaration of interests L.B-P is a founder, consultant, and holds privately held equity in Scorpion Therapeutics. D.E.F. has a financial interest in Soltego, a company developing salt-inducible kinase inhibitors for topical skin-darkening treatments that might be used for a broad set of human applications. The interests of L.B-P and D.E.F. were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. M.C.H. is on the SAB and holds equity in Alixia Therapeutics and is on the SAB of Minovia. T. P. is on the SAB of Faeth Therapeutics and consults for Dracen Pharmaceuticals. A.N.H receives research funding from Amgen, Blueprint Medicines, BridgeBio, Bristol-Myers Sqiub, C4 Therapeutics, Eli Lilly, Novartis, Nuvalent, Pfizer, Roche/Genentech, and Scorpion Therapeutics, and consults for Engine Biosciences, Nuvalent, TigaTx, and Tolremo Therapeutics., (Copyright © 2023 Elsevier Inc. All rights reserved.)