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NRF2 activation induces NADH-reductive stress, providing a metabolic vulnerability in lung cancer

Tommy Weiss-Sadan1, Maolin Ge1, Makiko Hayashi2

  • 1Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA.

Cell Metabolism
|February 25, 2023
PubMed

Insights

Activating the NRF2 pathway in lung cancer unexpectedly causes cell death by inducing reductive stress. This vulnerability can be targeted by inhibiting Complex I, offering new therapeutic strategies for NRF2-activated cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • The NRF2 (Nuclear factor erythroid 2-related factor 2) pathway is crucial for regulating oxidative stress in cancer, often activated by KEAP1 (Kelch-like ECH-associated protein 1) mutations.
  • The role of NRF2 in cancers with wild-type KEAP1 is less understood, representing a gap in knowledge for therapeutic development.

Purpose of the Study:

  • To investigate the function of the NRF2 pathway in non-small cell lung cancer (NSCLC) with wild-type KEAP1.
  • To identify potential metabolic vulnerabilities associated with NRF2 activation in NSCLC.

Main Methods:

  • Pharmacological inactivation of KEAP1 to induce NRF2 in over 50 NSCLC cell lines.
  • Genome-wide and targeted CRISPR screens to identify genes mediating NRF2 effects.
  • Cell viability assays and metabolic stress analyses, including Complex I inhibition.

Main Results:

  • Unexpectedly, NRF2 induction led to decreased cell viability in over 13% of NSCLC cell lines, an effect dependent on NRF2.
  • NRF2 was found to upregulate ALDH3A1 (aldehyde dehydrogenase 3 family member A1), an NAD+-consuming enzyme, leading to NADH-reductive stress.
  • Cells with activated NRF2 (either pharmacologically induced or via KEAP1 mutation) showed selective vulnerability to Complex I inhibition.

Conclusions:

  • NRF2 activation in NSCLC can induce a state of reductive stress, creating a metabolic vulnerability.
  • Targeting Complex I offers a potential therapeutic strategy for NSCLC with activated NRF2, regardless of KEAP1 mutation status.
  • Reductive stress is identified as a key metabolic vulnerability in NRF2-activated lung cancers.
Keywords:
NADH/NAD(+)NRF2-KEAP1 pathwayfunctional genomicnon-small cell lung canceroxidative phosphorylationreductive stress

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