Abstract 1416: CB-839, a novel potent and selective glutaminase inhibitor, has broad antiproliferative activity in cell lines derived from both solid tumors and hematological malignancies

Abstract

Abstract Many tumor cells utilize altered metabolic pathways to meet the bioenergetic and biosynthetic demands of rapid and sustained growth. One of the key nutrients that fuels tumor growth is the amino acid glutamine. It has long been recognized that the growth and survival of many tumor cell lines in vitro is dependent on extracellular glutamine. A critical step in the utilization of glutamine is its conversion to glutamate by the mitochondrial enzyme glutaminase. Glutamate and glutamate-derived metabolites in turn support a number of crucial cellular pathways including the citric acid cycle, redox balance and amino acid synthesis. CB-839 is a novel and selective inhibitor of glutaminase that has antitumor activity in preclinical models of triple negative breast cancer (TNBC), a tumor type that is particularly dependent on glutamine. Across a panel of breast cancer cell lines, the activity of CB-839 correlates with high expression of glutaminase, specifically the GAC splice variant but not the KGA splice variant, and low expression of glutamine synthetase (GLUL), an enzyme that converts glutamate to glutamine. This expression pattern is found in primary TNBC tumors suggesting a reliance on exogenous glutamine and glutaminase activity in vivo. To determine if other tumor types have a similar expression pattern, we undertook a systematic evaluation of GAC, KGA and GLUL expression across a diverse set of primary tumors using a normalized microarray dataset allowing comparison across a range of tumor and normal tissue samples. Elevated GAC and decreased GLUL expression relative to other tumor types or corresponding normal tissue was identified in a number of tumor types including non-small cell lung cancer, multiple myeloma, and non-Hodgkin's lymphoma. To explore whether this expression pattern predicts a reliance on glutamine and glutaminase, we tested the glutamine dependence and the activity of CB-839 on a panel of 72 cell lines representing 5 tumor types indicated by the primary tumor expression analysis. Across this cell line panel, the majority were dependent on glutamine showing either cell death, growth arrest or slowed growth after glutamine withdrawal. Similarly, CB-839 had antiproliferative activity in the majority of cell lines with IC50s in the range of 10-300 nM. Importantly, there was a strong correlation between glutamine dependence and response to 1 µM CB-839 as measured by relative cell growth or death (correlation coefficient 0.72, p<0.0001), suggesting that the glutamine requirement for tumor cell growth or survival is mediated by glutaminase and that this phenotype is consistent across numerous tumor types. These data suggest that CB-839 may have therapeutic activity in a range of tumor types that are glutamine dependent and motivate the clinical evaluation of this compound targeting a novel tumor survival pathway. Citation Format: Francesco Parlati, Susan D. Demo, Matthew I. Gross, Julie R. Janes, Evan R. Lewis, Andy L. MacKinnon, Mirna L.M. Rodriguez, Peter J. Shwonek, Taotao Wang, Jinfu Yang, Dong Zhang, Frances Zhao, Mark K. Bennett. CB-839, a novel potent and selective glutaminase inhibitor, has broad antiproliferative activity in cell lines derived from both solid tumors and hematological malignancies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1416. doi:10.1158/1538-7445.AM2014-1416