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SCD1 Inhibition Blocks the AKT-NRF2-SLC7A11 Pathway to Induce Lipid Metabolism Remodeling and Ferroptosis Priming in
Utsav Sen1, Charles Coleman2,3, Nishant Gandhi4
1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
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.
Insights
Concurrent STK11/KEAP1 mutations in KRAS-mutated lung adenocarcinoma (LUAD) promote resistance and poor outcomes. Inhibiting SCD1 shows promise by inducing ferroptosis and tumor regression in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Signaling
Background:
- Concurrent inactivating mutations in STK11 and KEAP1 are linked to primary therapy resistance and poor prognosis in KRAS-mutated lung adenocarcinoma (KRASmut-LUAD).
- This aggressive LUAD subset exhibits significant metabolic alterations, necessitating a deeper understanding of its underlying biology for effective treatment development.
Purpose of the Study:
- To elucidate the biological mechanisms driving aggressive KRASmut-LUAD with STK11/KEAP1 co-mutations.
- To identify potential therapeutic targets within the metabolic pathways dysregulated in this LUAD subset.
Main Methods:
- Transcriptomic analysis of 5498 "real-world" KRASmut-LUAD samples.
- Lipidomic and kinase array analyses in preclinical models.
- Investigated the effects of SCD1 inhibition on tumor growth, ferroptosis, and signaling pathways.
Main Results:
- STK11/KEAP1 co-mutation upregulated fatty acid and redox signaling, enriching for metabolic genes SCD1 and SLC7A11.
- High SCD1 and SLC7A11 expression correlated with poor prognosis in KRASmut-LUAD patients.
- SCD1 inhibition in preclinical models induced ferroptosis, altered fatty acid metabolism, downregulated SLC7A11 via AKT-GSK3β-NRF2 signaling, and caused tumor regression, enhancing erastin efficacy.
Conclusions:
- The SCD1-SLC7A11 axis plays a critical role in metabolic reprogramming and predicts poor outcomes in a specific subset of KRASmut-LUAD.
- Targeting SCD1 represents a potential therapeutic strategy for KRASmut-LUAD with STK11/KEAP1 co-mutations, possibly in combination with ferroptosis inducers.
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