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 KRAS<sup>MU</sup>/KEAP1<sup>WT</sup> cells but not in KRAS<sup>MU</sup>/KEAP1<sup>MU</sup> cells. Transcriptome sequencing and metabolome profiling pinpoint SAT1, the key enzyme in polyamine metabolism, as essential for this divergence. In KRAS<sup>MU</sup>/KEAP1<sup>WT</sup> 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<sup>MU</sup>/KEAP1<sup>MU</sup> 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<sup>MU</sup>/KEAP1<sup>WT</sup> resistant cells, patient-derived organoids, xenografts, and spontaneously tumorigenic mice, while KRAS<sup>MU</sup>/KEAP1<sup>MU</sup> 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.
Authors
- Qihai Sui (ORCID: https://orcid.org/0000-0003-4427-5340)
- Guangyao Shan (ORCID: https://orcid.org/0000-0002-2993-5817)
- Tao Lu (ORCID: https://orcid.org/0000-0002-8247-8387)
- Guoshu Bi (ORCID: https://orcid.org/0000-0003-2187-5271)
- Yunyi Bian (ORCID: https://orcid.org/0000-0003-3864-1199)
- Wei Guo (ORCID: https://orcid.org/0000-0001-8302-8292)
- Hong Fan (ORCID: https://orcid.org/0000-0002-2005-1150)
- Yanjun Yi
- Haochun Shi (ORCID: https://orcid.org/0009-0009-3471-0901)
- Jiaqi Liang (ORCID: https://orcid.org/0000-0002-4738-4238)
- Qun Wang (ORCID: https://orcid.org/0000-0003-4853-1727)
- Huan Zhang (ORCID: https://orcid.org/0009-0009-1420-0154)
- Wei Jiang (ORCID: https://orcid.org/0000-0003-0904-3990)
- Zhijie Xu (ORCID: https://orcid.org/0000-0003-2047-883X)
- Cheng Zhan (ORCID: https://orcid.org/0000-0001-8745-9276)
- Yuanliang Yan (ORCID: https://orcid.org/0000-0001-6610-3617)
Institutions
- Central South University (CN)
- Sun Yat-sen University (CN)
- Shanghai Jiao Tong University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Fudan University (CN)
- Shanghai Chest Hospital (CN)
- Fudan University Shanghai Cancer Center (CN)
- Shanxi Provincial Cancer Hospital (CN)
- Shanghai Public Health Clinical Center (CN)
- Sichuan Cancer Hospital (CN)
- Zhongshan Hospital of Xiamen University (CN)
- Zhongshan Hospital (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Cancer Hospital of Chinese Academy of Medical Sciences (CN)
- Xiangya Hospital Central South University (CN)
- YangPu Geriatric Hospital (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-11
- DOI
- https://doi.org/10.1038/s41467-025-65441-4
- Citations
- 2
- Primary Topic
- Polyamine Metabolism and Applications
- Type
- article
- Field-Weighted Citation Impact
- 1.61