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Activation of Oxidative Stress Response in Cancer Generates a Druggable Dependency on Exogenous Non-essential Amino

Sarah E LeBoeuf1, Warren L Wu1, Triantafyllia R Karakousi1

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

Cell Metabolism
|December 10, 2019
PubMed

Insights

Lung adenocarcinoma with KEAP1/NRF2 mutations depends on non-essential amino acids (NEAAs) due to Nrf2-driven glutamate secretion. Restricting NEAAs or glutamate offers a targeted therapy approach.

Area of Science:

  • Oncology
  • Metabolic pathways
  • Cancer metabolism

Background:

  • Tumorigenesis involves metabolic pathway rewiring, leading to nutrient dependencies.
  • KEAP1/NRF2-mutated lung adenocarcinoma activates oxidative stress response, requiring metabolic adaptations for antioxidant production.

Purpose of the Study:

  • To investigate the metabolic dependencies of cancers with high antioxidant capacity.
  • To identify therapeutic strategies targeting NRF2-activated lung adenocarcinoma.

Main Methods:

  • Analysis of metabolic rewiring in KEAP1/NRF2-mutated lung adenocarcinoma.
  • Investigating the role of Nrf2-dependent glutamate secretion via system xc- (XCT).
  • Evaluating therapeutic targeting through dietary restriction or enzymatic depletion of NEAAs and glutaminase inhibition.

Main Results:

  • Cancers with high antioxidant capacity exhibit dependency on exogenous non-essential amino acids (NEAAs).
  • Nrf2-driven glutamate secretion via XCT limits intracellular glutamate for NEAA synthesis.
  • Dietary restriction or enzymatic depletion of NEAAs, and glutaminase inhibition, show therapeutic potential.

Conclusions:

  • Nrf2-activated cancers have a specific dependency on exogenous NEAAs.
  • Targeting NEAA metabolism or glutamate synthesis presents a viable therapeutic strategy for NRF2-driven cancers.
Keywords:
Keap1NRF2amino acid synthesisasparaginaseglutamateglutaminaselung cancermetabolismnon-essential amino acidsoxidative stresssystem x(c)(−)

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