Glutaminase inhibition with telaglenastat (CB-839) improves treatment response in combination with ionizing radiation in head and neck squamous cell carcinoma models

Background: The effectiveness of ionizing radiation (IR) in treating head and neck squamous cell carcinoma (HNSCC) is limited by adaptive radioresistance, mechanisms of which remain poorly understood. Elevated glutaminase gene expression is associated with significantly reduced survival (p < 0.03). Telaglenastat (CB-839), a glutaminase inhibitor well-tolerated in Phase I/II cancer trials, was investigated for its potential to enhance the cellular response to IR in HNSCC models.

Methods: The study utilized three human HNSCC cell lines and two xenograft mouse models to evaluate the effects of combining telaglenastat with IR on radiation sensitivity. Key outcomes included cell survival, spheroid size, tumor growth, and metabolic and molecular changes.

Results:

Combination Effects: IR combined with telaglenastat significantly reduced cell survival (p ≤ 0.05), spheroid size (p ≤ 0.0001), and tumor growth in CAL-27 xenograft-bearing mice compared to vehicle (p ≤ 0.01), telaglenastat alone (p ≤ 0.05), or IR alone (p ≤ 0.01).

Metabolic Impact: Telaglenastat reduced the Oxygen Consumption Rate/Extracellular Acidification Rate ratio in CAL-27 and HN5 cells under glucose and glutamine conditions (p ≤ 0.0001).

Cellular Stress: Telaglenastat increased oxidative stress and DNA damage in irradiated CAL-27 cells.

Conclusions: These findings demonstrate that telaglenastat enhances the anti-tumor response to IR by increasing oxidative stress, DNA damage, and metabolic disruption. The preclinical efficacy and established safety profile of telaglenastat support further investigation of this combination therapy in HNSCC patients.