Systemic activation of NRF2 contributes to the therapeutic efficacy of clinically-approved KRAS-G12C anti-cancer drugs

Abstract

At physiologically-relevant concentrations, both clinically-approved KRASG12C inhibitors Sotorasib and Adagrasib also function as inducers of NRF2. The activation of NRF2 by KRAS-G12C inhibitors represents a unique example of anti-cancer drugs which positively regulate the activity of a protein normally considered to be an oncogene.

Key Findings

• KRAS-G12C inhibitors Sotorasib and Adagrasib function as NRF2 inducers
• NRF2 activation by these drugs promotes anti-cancer immunity — paradigm-shifting
• Systemic NRF2 induction repolarizes myeloid cells toward anti-cancer M1 lineage
• Major implications for combination chemotherapy trials

Clinical Significance

Citation

Baird, L. et al. (2025). Systemic activation of NRF2 contributes to KRAS-G12C drug efficacy. British Journal of Cancer.