title: Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer.
abstract: Glutamine serves as an important source of energy and building blocks for many tumor cells. The first 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). CB-839 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 activity was observed in an estrogen receptor-positive cell line, T47D, and only modest effects on glutamine consumption and downstream metabolites were observed. Across a panel of breast cancer cell lines, GAC protein expression and glutaminase activity were elevated in the majority of TNBC cell 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 not KGA) 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 HER2(+) cell line model, JIMT-1, both as a single agent and in combination with paclitaxel. Together, these data provide a strong rationale for the clinical investigation of CB-839 as a targeted therapeutic in patients with TNBC and other glutamine-dependent tumors.
authors: Authors' Affiliations: Calithera Biosciences, South San Francisco, California; and Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Matt I
authors: MI
authors: Gross
authors: Susan D
authors: SD
authors: Demo
authors: Jennifer B
authors: JB
authors: Dennison
authors: Lijing
authors: L
authors: Chen
authors: Tania
authors: T
authors: Chernov-Rogan
authors: Bindu
authors: B
authors: Goyal
authors: Julie R
authors: JR
authors: Janes
authors: Guy J
authors: GJ
authors: Laidig
authors: Evan R
authors: ER
authors: Lewis
authors: Jim
authors: J
authors: Li
authors: Andrew L
authors: AL
authors: Mackinnon
authors: Francesco
authors: F
authors: Parlati
authors: Mirna L M
authors: ML
authors: Rodriguez
authors: Peter J
authors: PJ
authors: Shwonek
authors: Eric B
authors: EB
authors: Sjogren
authors: Timothy F
authors: TF
authors: Stanton
authors: Taotao
authors: T
authors: Wang
authors: Jinfu
authors: J
authors: Yang
authors: Frances
authors: F
authors: Zhao
authors: Mark K
authors: MK
authors: Bennett
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D044482:Benzeneacetamides / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D005260:Female; D005972:Glutaminase / Q000037:antagonists & inhibitors*; D006801:Humans; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D018295:Neoplasms, Basal Cell / Q000188:drug therapy* / Q000473:pathology; D013440:Sulfides / Q000008:administration & dosage / Q000627:therapeutic use; D013830:Thiadiazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D044482:Benzeneacetamides; C000593334:CB-839; D004791:Enzyme Inhibitors; D013440:Sulfides; D013830:Thiadiazoles; C523193:bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide; D005972:Glutaminase