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

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2025年11月11日

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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

摘要

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, thereby inhibiting SAT1 expression. Our results further demonstrate that polyamine supplementation enhances KRAS-targeted therapy in KRAS^MU/KEAP1^WT resistant cells, patient-derived organoids, xenografts, and spontaneously tumorigenic mice, while KRAS^MU/KEAP1^MU 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.