1. Academic Validation
  2. Heterogeneity of glutamine metabolism in acquired-EGFR-TKI-resistant lung cancer

Heterogeneity of glutamine metabolism in acquired-EGFR-TKI-resistant lung cancer

  • Life Sci. 2022 Feb 15;291:120274. doi: 10.1016/j.lfs.2021.120274.
Suntae Kim 1 Jang Su Jeon 2 Yong June Choi 1 Ga Hee Baek 2 Sang Kyum Kim 2 Keon Wook Kang 3
Affiliations

Affiliations

  • 1 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
  • 2 College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea.
  • 3 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: [email protected].
Abstract

Aims: The purpose of this study was to evaluate the heterogeneities of glutamine metabolism in EGFR-TKI-resistant lung Cancer cells and its potential as a therapeutic target.

Main methods: Cell proliferation and cell cycle assays was performed by IncuCyte real-time analysis and flow cytometry, respectively. Tumor growth was assessed in xenografts implanted with HCC827 GR. An isotopologue analysis was conducted by LC-MS/MS using 13C-(U)-glutamine labeling to determine the amounts of metabolites. Cellular ATP and mitochondrial oxidative phosphorylation were determined by XFp analysis.

Key findings: We found that the cell growth of the two acquired EGFR-TKI-resistant lung Cancer cells lines (HCC827 GR and H292 ER) depends on glutamine. In HCC827 GR, glutamine deficiency caused reduced GSH synthesis and, subsequently, enhanced ROS generation relative to their parental cells, HCC827. On the other hand, in H292 ER, glutamine mainly acted as a carbon source for TCA-cycle intermediates, and its depletion led to reduced mitochondrial ATP production. CB-839, a specific GLS inhibitor, inhibited the latter's conversion of glutamine to glutamate and exerted enhanced anti-proliferating effects on the two acquired EGFR-TKI-resistant lung Cancer cell lines versus their parental cell lines. Moreover, oral administration of CB-839 significantly suppressed HCC827 GR tumor growth in the xenograft model.

Significance: These findings suggest that glutamine dependency in acquired EGFR-TKI-resistant lung Cancer is heterogeneous and that inhibition of glutamine metabolism by CB-839 may serve as a therapeutic tool for acquired EGFR-TKI-resistant lung Cancer.

Keywords

Acquired EGFR-TKI-resistant lung cancer; CB-839; CB-839 (Telaglenastat; Glutamine metabolism; PubChem CID: 71577426).

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