Sen Utsav, Coleman Charles, Gandhi Nishant, Jethalia Vrinda, Demircioglu Deniz, Elliott Andrew, Vanderwalde Ari M, Hayatt Omar, de Stanchina Elisa, Halmos Balazs, Ma Patrick C, Berisa Mirela, Hasson Dan, Sen Triparna
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Cancer Res. 2025 Jul 2;85(13):2485-2503. doi: 10.1158/0008-5472.CAN-24-2745.
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.
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.
STK11和KEAP1中的同时失活突变导致对治疗的原发性耐药，在KRAS突变的肺腺癌（KRASmut LUAD）中导致更差的预后，并与代谢改变相关。需要阐明这种侵袭性LUAD亚群的潜在生物学机制，以开发有效的治疗方法来改善患者预后。我们对5498例“真实世界”KRASmut LUAD进行的转录组分析表明，STK11/KEAP1共突变导致脂肪酸和氧化还原信号通路上调，以及代谢基因SCD1和SLC7A11的显著富集。SCD1和SLC7A11的高表达预示着KRASmut患者的预后不良。临床前模型中的转录组学、脂质组学和激酶阵列表明，SCD1抑制促进铁死亡，改变脂肪酸代谢，并通过AKT-GSK3β-NRF2信号通路下调SLC7A11。SCD1抑制导致异种移植瘤明显消退，并增强了铁死亡诱导剂埃拉斯汀的疗效。总体而言，本研究深入了解了SCD1-SLC7A11轴在调节代谢编程以及预测KRASmut LUAD基因定义亚群中患者预后不良方面的作用。
SCD1和SLC7A11是KRAS/STK11/KEAP1共突变肺腺癌的预后生物标志物和治疗靶点，这将重新聚焦机制研究并引领肺癌治疗策略。
