Romidepsin inhibits NRF2 and enhances the efficacy of adagrasib by inducing autophagic cell death in KRAS-mutant tumor cells.

Abstract

KRAS-mutant tumors remain a major challenge in cancer therapy. Although current targeted drugs show initial promise, their efficacy is often limited by the development of resistance. Therefore, identifying effective drug combinations to target KRAS-mutant tumors is of great significance. This study investigates the synergistic potential of romidepsin (RO), a class I HDAC inhibitor, in combination with adagrasib (ADA). In vitro experiments demonstrated that RO exhibits potent antitumor activity, with significant efficacy against KRAS-mutant cells. Mechanistic studies revealed that RO exerts its effect by suppressing NRF2. More importantly, its combination with ADA enhanced cytotoxicity and further suppressed NRF2 expression, resulting in increased ROS levels, induction of cytotoxic autophagy, and inhibition of the downstream AKT pathway. In vivo xenograft models confirmed that the combination of RO and ADA significantly reduced tumor growth. These findings suggest that RO and ADA act synergistically against KRAS-mutant tumors by suppressing NRF2, supporting their potential as a targeted combination strategy for KRAS-driven cancers.

Key Findings

• Romidepsin (RO), a class I HDAC inhibitor, exhibits potent antitumor activity against KRAS-mutant tumor cells by suppressing NRF2.
• Combination of romidepsin and adagrasib (ADA) enhances cytotoxicity, increases ROS levels, induces cytotoxic autophagy, and inhibits the AKT pathway.
• In vivo xenograft models show that the RO and ADA combination significantly reduces tumor growth in KRAS-mutant cancers.

Clinical Significance

Citation

Fu Wenying, Yan Ying, Tian Feiet al.. Romidepsin inhibits NRF2 and enhances the efficacy of adagrasib by inducing autophagic cell death in KRAS-mutant tumor cells. Bioorganic chemistry. 2026-Aug-15.