2. Academic Validation
  3. A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer

A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer

  • Elife. 2020 Oct 5;9:e56749. doi: 10.7554/eLife.56749.
Haojie Jin  # 1 2,  Siying Wang  # 1,  Esther A Zaal  # 3,  Cun Wang 1 2,  Haiqiu Wu 4,  Astrid Bosma 2,  Fleur Jochems 2,  Nikita Isima 2,  Guangzhi Jin 5,  Cor Lieftink 2,  Roderick Beijersbergen 2,  Celia R Berkers 3 6,  Wenxin Qin 1,  Rene Bernards 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Division of Molecular Carcinogenesis, Oncode Institute. The Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 3 Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, Netherlands.
  • 4 Department of Cell and Chemical Biology, Leiden University Medical Centre, Leiden, Netherlands.
  • 5 Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
  • 6 Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands.
  • # Contributed equally.
PMID: 33016874 DOI: 10.7554/eLife.56749
Abstract

The dependency of Cancer cells on glutamine may be exploited therapeutically as a new strategy for treating cancers that lack druggable driver genes. Here we found that human liver Cancer was dependent on extracellular glutamine. However, targeting glutamine addiction using the Glutaminase Inhibitor CB-839 as monotherapy had a very limited Anticancer effect, even against the most glutamine addicted human liver Cancer cells. Using a chemical library, we identified V-9302, a novel inhibitor of glutamine transporter ASCT2, as sensitizing glutamine dependent (GD) cells to CB-839 treatment. Mechanically, a combination of CB-839 and V-9302 depleted glutathione and induced Reactive Oxygen Species (ROS), resulting in Apoptosis of GD cells. Moreover, this combination also showed tumor inhibition in HCC xenograft mouse models in vivo. Our findings indicate that dual inhibition of glutamine metabolism by targeting both Glutaminase and glutamine transporter ASCT2 represents a potential novel treatment strategy for glutamine addicted liver cancers.

Keywords

CB-839; cancer biology; glutamine addiction; glutaminolysis; hepatocellular carcinoma; human.

Figures
Products