Abstract 4711: CB-839, a selective glutaminase inhibitor, synergizes with signal transduction pathway inhibitors to enhance anti-tumor activity
Authors: Rodriguez Mirna , Zhang Winter , Bennett Mark , Emberley Ethan , Gross Mathew , Janes Julie , MacKinnon Andrew , Pan Alison , Steggerda Susanne , Works Melissa , Parlati Francesco 
Published: August 2015

Many tumor cells utilize the amino acid glutamine to meet the elevated bioenergetic and biosynthetic demands of rapid cell growth. Glutamine is utilized by the mitochondrial enzyme glutaminase, which converts glutamine to glutamate. Glutamate is then used to fuel downstream metabolic pathways such as the TCA cycle, redox balance and amino acid synthesis. CB-839 is a novel and selective inhibitor of glutaminase that impacts multiple metabolic pathways downstream of glutamate and has anti-tumor activity in several preclinical models. In addition to its effect on metabolism, CB-839 treatment decreased mTORC1 signaling in triple negative breast cancer [Dennison et al. (2014) Keystone Tumor Metabolism Conference Abstract #1027] and multiple myeloma cells [MacKinnon et al. (2014) ASH Annual Meeting Abstract # 3429]. These studies suggest that nutrient deprivation by CB-839 treatment can be sensed by the mTORC1 pathway.

This observation motivated an evaluation of whether inhibitors of receptor tyrosine kinase signaling, the MAP kinase pathway or the PI3 kinase/mTOR pathway could combine favorably with CB-839 to inhibit proliferation. The pan receptor tyrosine kinase inhibitor pazopanib, or the mTORC1 inhibitor everolimus synergized with CB-839 to produce anti-proliferative effects in several renal cell carcinoma (RCC) cell lines (CI range: 0.09-0.85 for pazopanib/CB-839 and 0.48-0.54 for everolimus/CB-839). The EGFR inhibitor erlotinib also synergized with CB-839 to produce strong anti-proliferative effects in several non-small cell lung cancer (NSCLC) cell lines (combination index (CI) range: 0.39-0.75). CB-839 and the MEK inhibitor selumetinib showed strong synergy in the KRAS mutant NSCLC cell line H2122 (CI = 0.46), but weak synergy in the KRAS wild-type cell line H661 (CI = 0.9). These antiproliferative effects were associated with diminished mTORC1 signaling measured in NSCLC cells treated with CB-839, erlotinib, selumetinib or combinations of these agents. The in vitro synergistic CB-839 combinations were also evalutated in an in vivo H2122 NSCLC xenograft model where enhanced anti-tumor activity was observed when CB-839 was dosed together with either erlotinib or selumetinib.

CB-839 is currently in Phase 1 clinical development for the treatment of solid and hematological tumor types. This study is the first demonstration that CB-839 can be used in combination with signaling pathway inhibitors to increase the anti-tumor activity of these agents. These observations provide a rationale for testing combinations of CB-839 with either erlotinib or selumetinib in NSCLC patients and pazopanib or everolimus in RCC patients.

Citation Format: Mirna Rodriguez, Winter Zhang, Mark Bennett, Ethan Emberley, Mathew Gross, Julie Janes, Andrew MacKinnon, Alison Pan, Susanne Steggerda, Melissa Works, Francesco Parlati. CB-839, a selective glutaminase inhibitor, synergizes with signal transduction pathway inhibitors to enhance anti-tumor activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4711. doi:10.1158/1538-7445.AM2015-4711