Small Molecule Therapeutics Antitumor Activity of the Glutaminase Inhibitor CB-839 in Triple-Negative Breast Cancer

Glutamine serves as an important source of energy andbuilding blocks formany tumor cells. Thefirst step in glutamine utilization is its conversion to glutamate by the mitochondrial enzyme glutaminase. CB-839 is a potent, selective, and orally bioavailable inhibitor of both splice variants of glutaminase (KGA and GAC). CB839 had antiproliferative activity in a triple-negative breast cancer (TNBC) cell line, HCC-1806, that was associated with a marked decrease in glutamine consumption, glutamate production, oxygen consumption, and the steady-state levels of glutathione and several tricarboxylic acid cycle intermediates. In contrast, no antiproliferative activitywas observed in an estrogen receptor–positive cell line, T47D, and onlymodest effects on glutamine consumption and downstream metabolites were observed. Across a panel of breast cancer cell lines,GACprotein expression andglutaminase activitywere elevated in themajority of TNBCcell lines relative to receptor positive cells. Furthermore, the TNBC subtype displayed the greatest sensitivity to CB-839 treatment and this sensitivity was correlated with (i) dependence on extracellular glutamine for growth, (ii) intracellular glutamate and glutamine levels, and (iii)GAC (but notKGA) expression, a potential biomarker for sensitivity. CB-839 displayed significant antitumor activity in two xenograft models: as a single agent in a patient-derived TNBC model and in a basal like HER2þ cell line model, JIMT-1, both as a single agent and in combinationwith paclitaxel. Together, these data provide a strong rationale for the clinical investigation of CB839 as a targeted therapeutic in patients with TNBC and other glutamine-dependent tumors.Mol Cancer Ther; 13(4); 890–901. 2014 AACR.