Blockade of glutamine-dependent cell survival augments antitumor efficacy of CPI-613 in head and neck cancer

Liwei Lang, Fang Wang, Zhichun Ding, Xiangdong Zhao, Reid Loveless, Jin Xie, Chloe Shay, Peng Qiu, Yonggang Ke, Nabil F. Saba, Yong Teng

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background: Alterations in metabolism are one of the emerging hallmarks of cancer cells and targeting dysregulated cancer metabolism provides a new approach to developing more selective therapeutics. However, insufficient blockade critical metabolic dependencies of cancer allows the development of metabolic bypasses, thus limiting therapeutic benefits. Methods: A series of head and neck squamous cell carcinoma (HNSCC) cell lines and animal models were used to determine the efficacy of CPI-613 and CB-839 when given alone or in combination. Glutaminase 1 (GLS1) depletion was achieved by lentiviral shRNAs. Cell viability and apoptosis were determined in HNSCC cells cultured in 2D culture dish and SeedEZ™ 3D scaffold. Molecular alterations were examined by Western blotting and immunohistochemistry. Metabolic changes were assessed by glucose uptake, lactate production, glutathione levels, and oxygen consumption rate. Results: We show here that HNSCC cells display strong addiction to glutamine. CPI-613, a novel lipoate analog, redirects cellular activity towards tumor-promoting glutaminolysis, leading to low anticancer efficacy in HNSCC cells. Mechanistically, CPI-613 inhibits the tricarboxylic acid cycle by blocking the enzyme activities of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, which upregulates GLS1 and eventually promotes the compensatory role of glutaminolysis in cancer cell survival. Most importantly, the addition of a GLS1 inhibitor CB-839 to CPI-613 treatment abrogates the metabolic dependency of HNSCC cells on glutamine, achieving a synergistic anticancer effect in glutamine-addicted HNSCC. Conclusions: These findings uncover the critical role of GLS1-mediated glutaminolysis in CPI-613 treatment and suggest that the CB-839 and CPI-613 combination may potentiate synergistic anticancer activity for HNSCC therapeutic gain.

Original languageEnglish (US)
Article number393
JournalJournal of Experimental and Clinical Cancer Research
Volume40
Issue number1
DOIs
StatePublished - Dec 2021

Keywords

  • CB-839
  • CPI-613
  • Combined targeting
  • GLS1
  • Glutaminolysis
  • HNSCC

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Blockade of glutamine-dependent cell survival augments antitumor efficacy of CPI-613 in head and neck cancer'. Together they form a unique fingerprint.

Cite this