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

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 KRASMU/KEAP1WT cells but not in KRASMU/KEAP1MU cells. Transcriptome sequencing and metabolome profiling pinpoint SAT1, the key enzyme in polyamine metabolism, as essential for this divergence. In KRASMU/KEAP1WT 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 KRASMU/KEAP1MU cells, activated JNK promotes the degradation of NRF2, thereby inhibiting SAT1 expression. Our results further demonstrate that polyamine supplementation enhances KRAS-targeted therapy in KRASMU/KEAP1WT resistant cells, patient-derived organoids, xenografts, and spontaneously tumorigenic mice, while KRASMU/KEAP1MU models require lentivirus or adeno-associated virus-mediated SAT1 overexpression prior to polyamine treatment, to augment ferroptosis and drug sensitivity. Our findings highlight SAT1-mediated polyamine metabolism as a promising target in precision treatments for KRAS-mutant cancers. Resistance to KRAS-targeted therapies is a challenge, especially with co-mutations like KEAP1. Here, the authors show that increasing polyamine metabolism enhances KRAS-targeted therapy efficacy but requires also increasing the polyamine-metabolism SAT1 enzyme in KEAP1-mutant context.