Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma
| Autor: | Wenhao Jiang, Haixiang Pei, Jing Chen, Feixiong Cheng, Zhenyu Cai, Kun Li, Xiufeng Pang, Haigang Wu, Yihua Chen, Jie Feng, Mingyao Liu, Kewen Hu, Jing Lv, Paul J. Chiao, Jieqiong Wang |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Lung Neoplasms Amino Acid Transport System y+ Cystine Mice Nude Adenocarcinoma of Lung Antineoplastic Agents Apoptosis Synthetic lethality SLC7A11 medicine.disease_cause Proto-Oncogene Proteins p21(ras) Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Animals Humans Mice Inbred BALB C biology Chemistry General Medicine Glutathione Endoplasmic Reticulum Stress Xenograft Model Antitumor Assays digestive system diseases 030104 developmental biology A549 Cells Tumor progression 030220 oncology & carcinogenesis Mutation Cancer cell biology.protein Cancer research KRAS Research Article |
| Zdroj: | J Clin Invest |
| ISSN: | 1558-8238 0021-9738 |
| Popis: | Oncogenic KRAS is a major driver in lung adenocarcinoma (LUAD) that has yet to be therapeutically conquered. Here we report that the SLC7A11/glutathione axis displays metabolic synthetic lethality with oncogenic KRAS. Through metabolomics approaches, we found that mutationally activated KRAS strikingly increased intracellular cystine levels and glutathione biosynthesis. SLC7A11, a cystine/glutamate antiporter conferring specificity for cystine uptake, was overexpressed in patients with KRAS-mutant LUAD and showed positive association with tumor progression. Furthermore, SLC7A11 inhibition by either genetic depletion or pharmacological inhibition with sulfasalazine resulted in selective killing across a panel of KRAS-mutant cancer cells in vitro and tumor growth inhibition in vivo, suggesting the functionality and specificity of SLC7A11 as a therapeutic target. Importantly, we further identified a potent SLC7A11 inhibitor, HG106, that markedly decreased cystine uptake and intracellular glutathione biosynthesis. Furthermore, HG106 exhibited selective cytotoxicity toward KRAS-mutant cells by increasing oxidative stress– and ER stress–mediated cell apoptosis. Of note, treatment of KRAS-mutant LUAD with HG106 in several preclinical lung cancer mouse models led to marked tumor suppression and prolonged survival. Overall, our findings reveal that KRAS-mutant LUAD cells are vulnerable to SLC7A11 inhibition, offering potential therapeutic approaches for this currently incurable disease. |
| Databáze: | OpenAIRE |
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