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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

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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 2

SLC7A11 is overexpressed in KRAS-mutant LUAD.

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SLC7A11 is overexpressed in KRAS-mutant LUAD.
(A) mRNA levels of SLC7A11...
(A) mRNA levels of SLC7A11 and NRF2. (B) Protein levels of SLC7A11 and Nrf2. For each cell pair, SLC7A11 and Nrf2 are contemporaneous immunoblots that run in parallel from the same biological replicate. (C) SLC7A11 and Nrf2 expression in normal lung tissues (N) and tumors (T) from LSL-KrasG12D mice (n = 4). p-ERK was stripped, and the same membrane was then immunoblotted for total ERK. (D) Nrf2 and SLC7A11 expression in mouse embryonic fibroblasts (MEFs). MEFs were generated from LSL-KrasG12D mice and induced by adenovirus-Cre (Ad-cre) for 48 hours (n = 3). p-ERK and total ERK are contemporaneous immunoblots that run in parallel from the same biological replicate. (E) Nrf2 and SLC7A11 expression upon KRAS silencing. For individual cell lines, KRAS, SLC7A11, and Nrf2 are contemporaneous immunoblots that run in parallel from the same biological replicate. (F) SLC7A11 suppression upon genetic depletion of Nrf2. Nrf2-sg1 and Nrf2-sg2 represent 2 individual small guide RNAs targeting Nrf2 for editing. (G and H) SLC7A11 and Nrf2 expression upon blockade of KRAS signaling at the mRNA (G) and protein levels (H). A549 cells were treated with LY294002 (1 μM, PI3K inhibitor), afuresertib (5 μM, Akt inhibitor), dabrafenib (20 μM, Raf inhibitor), AZD6244 (20 nM, MEK inhibitor), and RBC8 (10 μM, Ral GTPase inhibitor) for 48 hours, respectively. Results are shown as mean ± SD of biological triplicates. **P < 0.01 by unpaired, 2-tailed Student’s t tests. (I) SLC7A11 expression in clinical samples. Scale bars: 50 μm. (J) Box plots showing SLC7A11 IHC scores. The horizontal lines represent the median; the bottom and top of the boxes represent the 25th and 75th percentiles, respectively; and the vertical bars represent the range of the data. (K) Box plot of SLC7A11 expression in clinical tumors. Stage classification of LUAD refers to the TNM classification. *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA with Tukey’s multiple-comparisons test.

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