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. 2025 Jul 2;85(13):2485-2503.
doi: 10.1158/0008-5472.CAN-24-2745.

SCD1 Inhibition Blocks the AKT-NRF2-SLC7A11 Pathway to Induce Lipid Metabolism Remodeling and Ferroptosis Priming in Lung Adenocarcinoma

Utsav Sen  1 , Charles Coleman  2   3 , Nishant Gandhi  4 , Vrinda Jethalia  2   3 , Deniz Demircioglu  1   2   3 , Andrew Elliott  4 , Ari M Vanderwalde  4 , Omar Hayatt  5 , Elisa de Stanchina  5 , Balazs Halmos  6 , Patrick C Ma  7 , Mirela Berisa  8 , Dan Hasson  1   2   3 , Triparna Sen  1   2
Affiliations

SCD1 Inhibition Blocks the AKT-NRF2-SLC7A11 Pathway to Induce Lipid Metabolism Remodeling and Ferroptosis Priming in Lung Adenocarcinoma

Utsav Sen et al. Cancer Res. .

Abstract

Concurrent inactivating mutations in STK11 and KEAP1 drive primary resistance to therapies, leading to worse outcomes in KRAS-mutated lung adenocarcinoma (KRASmut LUAD), and are associated with metabolic alterations. Elucidation of the underlying biology of this aggressive LUAD subset is needed to develop effective treatments to improve patient outcomes. Our transcriptomic analysis of 5,498 "real-world" KRASmut LUADs demonstrated that STK11/KEAP1 co-mutation led to upregulation of fatty acid and redox signaling pathways and considerable enrichment of the metabolic genes SCD1 and SLC7A11. High expression of SCD1 and SLC7A11 predicted poor prognosis in KRASmut patients. Transcriptomics, lipidomics, and kinase arrays in preclinical models demonstrated that SCD1 inhibition promoted ferroptosis, altered fatty acid metabolism, and downregulated SLC7A11 via AKT-GSK3β-NRF2 signaling. SCD1 inhibition caused appreciable tumor regression in xenografts and augmented the efficacy of the ferroptosis inducer erastin. Overall, this study provides insights into the role of the SCD1-SLC7A11 axis in regulating metabolic programming and predicting poor patient outcomes in a genetically defined subset of KRASmut LUAD.

Significance: SCD1 and SLC7A11 are prognostic biomarkers and therapeutic targets for KRAS/STK11/KEAP1 co-mutant lung adenocarcinoma, which will refocus mechanistic studies and lead to treatment strategies for lung cancer.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest:

TS has received research grants from Jazz Pharmaceuticals and Debiopharm. NG, AE, AV are employees of Caris. All other authors have no relevant disclosures.

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