Targeting polyamine metabolism and ferroptosis enhances the efficacy of KRAS-targeted therapy depending on KEAP1 status.

ABSTRACT: The resistance to KRAS-targeted therapies, particularly due to co-occurring gene mutations, remains a significant challenge. Through a metabolite library screening, we reveal that polyamines sensitize KRAS inhibitors only in KRAS^MU/KEAP1^WT cells but not in KRAS^MU/KEAP1^MU cells. Transcriptome sequencing and metabolome profiling pinpoint SAT1, the key enzyme in polyamine metabolism, as essential for this divergence. In KRAS^MU/KEAP1^WT context, treatment of KRAS inhibitors activates JNK/c-Jun pathway and SAT1 expression, while the augmented SAT1 facilitates polyamine metabolism and KRAS inhibitors-induced ferroptosis. Conversely, in KRAS^MU/KEAP1^MU cells, activated JNK promotes the degradation of NRF2, there

SUBMITTER: Bian Y 

PROVIDER: S-EPMC12606100 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature