2. Academic Validation
  3. Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-W451275
    99.95%, SLC7A11 Inhibitor