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

Molecular Cancer Therapeutics - Tập 13 Số 4 - Trang 890-901 - 2014
Matt I. Gross1, Susan D. Demo1, Jennifer B. Dennison1, Lijing Chen1, Tania Chernov-Rogan1, Bindu Goyal1, Julie Janes1, Guy J. Laidig1, Evan R. Lewis1, Jun Li1, Andrew L. MacKinnon1, Francesco Parlati1, Mirna L.M. Rodriguez1, Peter J. Shwonek1, Eric B. Sjogren1, Timothy F. Stanton1, Taotao Wang1, Jinfu Yang1, Frances Zhao1, Mark K. Bennett1
1Authors' Affiliations: 1Calithera Biosciences, South San Francisco, California; and 2Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas

Tóm tắt

AbstractGlutamine 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. Mol Cancer Ther; 13(4); 890–901. ©2014 AACR.

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Molecular Cancer Therapeutics

Tập 13 Số 4

890-901

Thông tin tác giả