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

Yunyi Bian,Guangyao Shan,Guoshu Bi,Zhijie Xu,Jiaqi Liang,Yuanliang Yan,Wei Guo,Qihai Sui,Yanjun Yi,Haochun Shi,Tao Lu,Huan Zhang,Qun Wang,Hong Fan,Wei Jiang,Cheng Zhan

Published 2025 in Nature Communications

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 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.

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