Glutaminase inhibition with telaglenastat (CB-839) improves treatment response in combination with ionizing radiation in head and neck squamous cell carcinoma models. (1st April 2021)

• Record Type: Journal Article
• Authors: Wicker, Christina A.; Hunt, Brian G.; Krishnan, Sunil; Aziz, Kathryn; Parajuli, Shobha; Palackdharry, Sarah; Elaban, William R.; Wise-Draper, Trisha M.; Mills, Gordon B.; Waltz, Susan E.; Takiar, Vinita
• Is Part Of: Cancer letters. Volume 502(2021)
• Page Start: 180
• Page End: 188
• Publication Date: 2021-04-01
• Subjects: Combinatorial therapy -- Radiosensitivity -- Radioresistance -- Small molecule inhibitor -- Preclinical models; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2020.12.038
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: The efficacy of ionizing radiation (IR) for head and neck cancer squamous cell carcinoma (HNSCC) is limited by poorly understood mechanisms of adaptive radioresistance. Elevated glutaminase gene expression is linked to significantly reduced survival (p < 0.03). The glutaminase inhibitor, telaglenastat (CB-839), has been tested in Phase I/II cancer trials and is well tolerated by patients. This study investigated if telaglenastat enhances the cellular response to IR in HNSCC models. Using three human HNSCC cell lines and two xenograft mouse models, we examined telaglenastat's effects on radiation sensitivity. IR and telaglenastat combinatorial treatment reduced cell survival (p ≤ 0.05), spheroid size (p ≤ 0.0001) and tumor growth in CAL-27 xenograft bearing mice relative to vehicle (p ≤ 0.01), telaglenastat (p ≤ 0.05) or IR (p ≤ 0.01) monotherapy. Telaglenastat significantly reduced the Oxygen Consumption Rate/Extracellular Acidification Rate ratio in CAL-27 and HN5 cells in the presence of glucose and glutamine (p ≤ 0.0001). Telaglenastat increased oxidative stress and DNA damage in irradiated CAL-27 cells. These data suggest that combination treatment with IR and telaglenastat leads to an enhanced anti-tumor response. This pre-clinical data, combined with the established safety of telaglenastat justifies further investigation for the combination in HNSCC patients. Highlights: CAL-27, FaDu, and HN5 have glutamine dependent proliferation. Telaglenastat inhibits HNSCC spheroid growth. Telaglenastat increases IR-induced cell death. Telaglenastat decreases aerobic respiration. Combination of telaglenastat and IR reduces tumor size in CAL-27 xenograft mice.