Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma
Kewen Hu, … , Mingyao Liu, Xiufeng Pang
Kewen Hu, … , Mingyao Liu, Xiufeng Pang
Published December 24, 2019
Citation Information: J Clin Invest. 2020;130(4):1752-1766. https://doi.org/10.1172/JCI124049.
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Research Article Oncology

Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma

Abstract

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.

Authors

Kewen Hu, Kun Li, Jing Lv, Jie Feng, Jing Chen, Haigang Wu, Feixiong Cheng, Wenhao Jiang, Jieqiong Wang, Haixiang Pei, Paul J. Chiao, Zhenyu Cai, Yihua Chen, Mingyao Liu, Xiufeng Pang

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Figure 5

Identification of HG106 as a potent SLC7A11 inhibitor.

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Identification of HG106 as a potent SLC7A11 inhibitor. (A) Chemical stru...
(A) Chemical structure of HG106. (B and C) HG106 dose-dependently inhibited cystine uptake and GSH level. A549 and H441 cells were treated with HG106 and sulfasalazine (1 mM). Relative cystine uptake and GSH levels were calculated by setting the values of the vehicle control group as 100%. (D) Metabolic pathway enrichment in A549 cells after HG106 treatment. A549 cells were treated with 5 μM HG106 for 6 hours. Cell lysates were subjected to metabolomic profiling. For metabolite pathway enrichment analysis, subsets of significantly affected metabolites were chosen. The bar plot shows the top 10 enriched pathways (n = 4). (E) Significantly changed metabolites involved in GSH biosynthesis are shown in the heatmap (n = 4). Changes in cystine and glutathione between the vehicle control– and HG106-treated groups are shown according to the metabolomic data. (F) Effect of β-mercaptoethanol (β-ME, 100 μM) and l-cysteine (5 mM) on HG106-induced cell death in H441 cells. H441 cells were treated with an HG106 concentration gradient with or without β-ME and l-cysteine for 72 hours, and cell viability was measured. (G) Effect of SLC7A11 knockdown by RNA interference on HG106-induced cell death. H441 cells were treated with the indicated concentrations of HG106 72 hours after transfection with SLC7A11 siRNAs or a scrambled siRNA. Relative cell viability was calculated by setting the values of the siControl group as 100%. All data are representative of at least 2 independent experiments, and shown as mean ± SD of biological triplicates. *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA with Tukey’s multiple-comparisons test (B, C, and G) or by unpaired, 2-tailed Student’s t tests (E).