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Activation of the NRF2 antioxidant program sensitizes tumors to G6PD inhibition

Hongyu Ding1, Zihong Chen2,3,4, Katherine Wu1

  • 1Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.

Science Advances
|November 17, 2021
PubMed

Insights

Glucose-6-phosphate dehydrogenase (G6PD) is a key dependency in cancers with activated NRF2. Inhibiting G6PD disrupts the tricarboxylic acid (TCA) cycle, offering a new therapeutic strategy for NRF2-driven cancers.

Area of Science:

  • Oncology
  • Metabolic pathways
  • Cancer metabolism

Background:

  • The KEAP1/NRF2 pathway regulates cellular redox homeostasis and is frequently activated in cancers due to KEAP1 mutations.
  • NRF2 activation is linked to aggressive disease and resistance to cancer therapies.
  • Identifying metabolic vulnerabilities in NRF2-activated cancers is crucial for developing novel treatments.

Purpose of the Study:

  • To identify metabolic dependencies in cancers characterized by NRF2 pathway activation.
  • To explore the role of Glucose-6-phosphate dehydrogenase (G6PD) in these cancers.
  • To investigate therapeutic strategies targeting metabolic vulnerabilities in NRF2-activated cancers.

Main Methods:

  • A metabolism-focused CRISPR screen was employed to identify essential genes in NRF2-activated cancer models.
  • The function of Glucose-6-phosphate dehydrogenase (G6PD) was investigated, including its role in the oxidative pentose phosphate pathway.
  • The impact of G6PD inhibition on tricarboxylic acid (TCA) cycle intermediates and tumor growth was assessed in vitro and in vivo.
  • Combined therapeutic strategies involving G6PD inhibition and glutaminase inhibition were evaluated.

Main Results:

  • G6PD was identified as a significant metabolic dependency in cancers with NRF2 activation.
  • G6PD catalyzes the rate-limiting step of the oxidative pentose phosphate pathway, producing NADPH and nucleotide precursors.
  • Loss of G6PD led to TCA intermediate depletion due to the upregulation of alternative NADPH-producing enzymes (malic enzyme and isocitrate dehydrogenase).
  • G6PD impairment suppressed tumor growth in KEAP1-mutant cancers, an effect potentiated by glutaminase inhibition-induced TCA depletion.

Conclusions:

  • G6PD is a critical metabolic vulnerability in NRF2-activated cancers.
  • Targeting G6PD can induce TCA intermediate depletion, representing a potential therapeutic strategy.
  • Combination therapy involving G6PD inhibition and glutaminase inhibition shows promise for treating NRF2-driven cancers.

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