Activation of the NRF2 antioxidant program sensitizes tumors to G6PD inhibition

Hongyu Ding, Zihong Chen, Katherine Wu, Shih Ming Huang, Warren L. Wu, Sarah E. LeBoeuf, Ray G. Pillai, Joshua D. Rabinowitz, Thales Papagiannakopoulos

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

The KEAP1/NRF2 pathway promotes metabolic rewiring to support redox homeostasis. Activation of NRF2 occurs in many cancers, often due to KEAP1 mutations, and is associated with more aggressive disease and treatment resistance. To identify metabolic dependencies in cancers with NRF2 activation, we performed a metabolism-focused CRISPR screen. Glucose-6-phosphate dehydrogenase (G6PD), which was recently shown to be dispensable in Ras-driven tumors, was a top dependency. G6PD catalyzes the committed step of the oxidative pentose phosphate pathway that produces NADPH and nucleotide precursors, but neither antioxidants nor nucleosides rescued. Instead, G6PD loss triggered tricarboxylic acid (TCA) intermediate depletion because of up-regulation of the alternative NADPH-producing enzymes malic enzyme and isocitrate dehydrogenase. In vivo, G6PD impairment markedly suppressed KEAP1 mutant tumor growth, and this suppression was further augmented by TCA depletion by glutaminase inhibition. Thus, G6PD inhibition–induced TCA depletion is a therapeutic vulnerability of NRF2-activated cancer.

Original languageEnglish (US)
Article numbereabk1023
JournalScience Advances
Volume7
Issue number47
DOIs
StatePublished - Nov 2021

All Science Journal Classification (ASJC) codes

  • General

Fingerprint

Dive into the research topics of 'Activation of the NRF2 antioxidant program sensitizes tumors to G6PD inhibition'. Together they form a unique fingerprint.

Cite this