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 3

Silencing SLC7A11 selectively kills KRAS-mutant LUAD cells.

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Silencing SLC7A11 selectively kills KRAS-mutant LUAD cells. (A) Effects ...
(A) Effects of SLC7A11 depletion on cell survival. Isogenic cells were transfected with SLC7A11 siRNAs (siSLC7A11) or a scrambled siRNA (siControl). The knockdown efficiency of siSLC7A11 was examined by immunoblotting. Cell viability was measured 72 hours after transfection. Relative cell viability was calculated by setting the values of the siControl-alone group as 100%. (B) Effects of SLC7A11 depletion on ROS production. Relative ROS production was calculated by setting the values of the siControl-alone group as 100%. (C) SLC7A11 depletion led to selective toxicity toward KRAS-mutant cancer cell lines. Six KRAS-mutant and 9 WT cancer cell lines (see Supplemental Table 3) were transfected with siSLC7A11 or a scrambled siRNA. The percent cell viability is relative to the untreated controls. (D) Inhibitory effects of sulfasalazine (SAS) on isogenic cell lines. (E) SAS treatment led to selective toxicity toward KRAS-mutant cancer cells. Seven KRAS-mutant and 7 WT cancer cell lines were treated with SAS for 72 hours. Dots indicate IC50 value of each cell line. (F) Colony formation of A549 cells after SAS treatment. A549 cells were plated in 6-well plates and treated with the indicated concentrations of SAS for 7 days. The relative number of colonies was calculated by normalization to untreated group as 100%. Scale bar: 0.5 cm. (G) Effect of SAS on A549 cell soft agar colony formation. A549 cells were uniformly dispersed in agar and treated with the indicated concentrations of SAS for 21 days. The medium containing SAS was changed twice a week. At the end of the experiment, the colonies were photographed. Scale bar: 2 mm. All data are representative of 3 independent experiments and shown as mean ± SD of biological triplicates. *P < 0.05, **P < 0.01, ***P < 0.001 by unpaired, 2-tailed Student’s t tests.