State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Division of Molecular Carcinogenesis, Oncode Institute. The Netherlands Cancer Institute, Amsterdam, Netherlands.
Elife. 2020 Oct 5;9:e56749. doi: 10.7554/eLife.56749.
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.
癌细胞对谷氨酰胺的依赖性可以被开发为一种新的治疗策略，用于治疗缺乏可用药驱动基因的癌症。在这里，我们发现人类肝癌依赖于细胞外谷氨酰胺。然而，使用谷氨酰胺酶抑制剂 CB-839 作为单一疗法来靶向谷氨酰胺成瘾，其抗癌效果非常有限，即使是针对最依赖谷氨酰胺的人类肝癌细胞也是如此。我们使用化学文库发现了 V-9302，一种新型的谷氨酰胺转运体 ASCT2 抑制剂，可使依赖谷氨酰胺的 (GD) 细胞对 CB-839 治疗敏感。从机制上讲，CB-839 和 V-9302 的联合使用会耗尽谷胱甘肽并诱导活性氧 (ROS)，导致 GD 细胞凋亡。此外，这种联合治疗在 HCC 异种移植小鼠模型中也显示出了肿瘤抑制作用。我们的研究结果表明，通过同时靶向谷氨酰胺酶和谷氨酰胺转运体 ASCT2 双重抑制谷氨酰胺代谢可能代表一种治疗谷氨酰胺成瘾性肝癌的新潜在治疗策略。
