2. Academic Validation
  3. Activation of the NRF2 antioxidant program sensitizes tumors to G6PD inhibition

Activation of the NRF2 antioxidant program sensitizes tumors to G6PD inhibition

  • Sci Adv. 2021 Nov 19;7(47):eabk1023. doi: 10.1126/sciadv.abk1023.
Hongyu Ding 1,  Zihong Chen 2 3 4,  Katherine Wu 1,  Shih Ming Huang 1,  Warren L Wu 1,  Sarah E LeBoeuf 1,  Ray G Pillai 1 5 6,  Joshua D Rabinowitz 2 3 4,  Thales Papagiannakopoulos 1 7
Affiliations

Affiliations

  • 1 Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
  • 2 Lewis Sigler Institute for Integrative Genomics, Princeton University, Washington Road, Princeton, NJ 08544, USA.
  • 3 Department of Chemistry, Princeton University, Washington Road, Princeton, NJ 08544, USA.
  • 4 Ludwig Institute for Cancer Research, Princeton Branch, Princeton University, 91 Prospect Avenue, Princeton, NJ 08544, USA.
  • 5 Division of Pulmonary and Critical Care Medicine, Department of Medicine, VA New York Harbor Healthcare System, 423 East 23rd Avenue, New York, NY 10016, USA.
  • 6 Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
  • 7 Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA.
PMID: 34788087 DOI: 10.1126/sciadv.abk1023
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.

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