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

  • J Clin Invest. 2020 Apr 1;130(4):1752-1766. doi: 10.1172/JCI124049.
Kewen Hu  1  2 ,  Kun Li  1 ,  Jing Lv  1 ,  Jie Feng  3 ,  Jing Chen  4 ,  Haigang Wu  1 ,  Feixiong Cheng  5  6  7 ,  Wenhao Jiang  1 ,  Jieqiong Wang  2 ,  Haixiang Pei  1 ,  Paul J Chiao  8 ,  Zhenyu Cai  9 ,  Yihua Chen  1 ,  Mingyao Liu  1 ,  Xiufeng Pang  1
Affiliations
  • 1. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
  • 2. Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 3. Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
  • 4. Key Laboratory of Reproduction and Genetics in Ningxia, Ningxia Medical University, Yinchuan, China.
  • 5. Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
  • 6. Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
  • 7. Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
  • 8. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 9. National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
PMID: 31874110 DOI: 10.1172/JCI124049
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.

Keywords
Cancer; Drug therapy; Oncology.
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