Glutaminase Inhibition as a Novel Radiosensitizer in Triple Negative Breast Cancer

Triple-negative breast cancer (TNBC) is the most aggressive subtype and accounts for 15-20% of breast cancer cases. TNBC lacks expression of the estrogen, progesterone, and human epidermal growth factor receptor 2/neu (HER2/neu) receptors. Due to the lack of these receptors, targeted therapies are virtually ineffective. In addition, due to their aggressive nature, standard therapy options are limited by the development of resistance making TNBC very challenging to treat, highlighting the need for new therapeutic approaches. TNBCs undergo metabolic alterations to support growth and survival, one of which is glutamine addiction. TNBCs have been shown to demonstrate increased levels of GLS mRNA, which correlates with their dependence on exogenous glutamine for growth and survival. This study examined whether inhibiting glutamine metabolism enhances radiotherapy (RT) efficacy against TNBC. In two TNBC cell lines (MDA-MB-231 and 4T1), glutamine deprivation and the glutaminase (GLS) inhibitor CB-839 combined with ionizing radiation (IR) reduced colony formation in the combination treatment was significantly more effective than either treatment alone. In a murine model of TNBC, this combination significantly decreased mammary fat pad tumor growth. These findings demonstrate that inhibiting glutamine metabolism combined with RT represents a promising therapeutic strategy that could improve treatment outcomes in TNBC patients who currently have limited effective treatment options.