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Novel NRF2-activated cancer treatments utilizing synthetic lethality

Liam Baird1,2, Thomas W Kensler3, Masayuki Yamamoto1,2,4

  • 1Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.

IUBMB Life
|October 6, 2022
PubMed

Insights

The KEAP1-NRF2 pathway is crucial for cellular stress response and frequently mutated in aggressive cancers. Targeting NRF2-activated tumors with synthetic lethality offers a promising new therapeutic strategy.

Area of Science:

  • Molecular Biology
  • Oncology
  • Drug Discovery

Background:

  • The KEAP1-NRF2 pathway governs the cellular response to oxidative and electrophilic stresses.
  • Activating mutations in this pathway are common in aggressive human cancers, leading to poor patient prognosis.
  • NRF2-activated tumors exhibit resistance to current anti-cancer treatments, necessitating novel therapeutic approaches.

Approach:

  • This review discusses mechanisms of tumor resistance driven by NRF2 hyperactivation.
  • It explores how NRF2 hyperactivation confers resistance to both classical chemotherapeutics and immune checkpoint inhibitors.
  • The review proposes a synthetic lethal strategy utilizing NRF2-target gene-dependent prodrug bioactivation.

Key Points:

  • NRF2 hyperactivation contributes to treatment resistance in various cancers.
  • Synthetic lethality offers a targeted approach to exploit NRF2-driven vulnerabilities.
  • Prodrugs bioactivated by NRF2 target genes can selectively kill cancer cells.

Conclusions:

  • Developing therapies targeting NRF2-activated cancers is critical due to their aggressive nature and treatment resistance.
  • A synthetic lethal strategy offers a promising avenue for specifically enhancing toxicity in these tumors.
  • This approach holds potential for treating previously untreatable NRF2-hyperactivated human cancers.
Keywords:
KEAP1NFE2L2NRF2bioactivationcancermitomycin Coxidative stressprodrugstress responsesynthetic lethal

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