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Gene EditingCancer Drug ResistanceTherapeutics

CRISPR-directed therapy restores chemotherapy sensitivity in lung tumors with NRF2 mutation

Molecular Therapy Oncology

Abstract

Researchers used CRISPR to selectively knock down a cancer-specific version of NRF2, restoring chemotherapy efficacy in mouse models of lung squamous cell carcinoma. They exploited a tumor mutation (R34G) that creates a unique PAM site. Modest but durable editing (20-40%) was sufficient to slow tumor growth and re-sensitize them to carboplatin-paclitaxel.

Key Findings

  • CRISPR-Cas9 selectively targets tumor-specific NRF2 R34G mutation
  • R34G creates unique PAM site for tumor-selective gene editing
  • Even modest 20-40% editing restores chemotherapy response
  • Lipid nanoparticle delivery with minimal off-target effects
  • CorriXR Therapeutics pursuing IND-enabling studies

Clinical Significance

Breakthrough CRISPR approach selectively disabling cancer-driving NRF2 mutations. Could become first CRISPR therapy targeting NRF2 in cancer.

Citation

Banas, K. et al. (2025). CRISPR-directed therapy for NRF2-mutant lung tumors. Molecular Therapy Oncology.

DOI: 10.1016/j.omton.2025.201079