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      Targeting glutamine metabolism in PIK3CA mutant colorectal cancers

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      Genes & Diseases
      Chongqing Medical University

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          Abstract

          We recently reported that PIK3CA mutant colorectal cancers (CRCs) are addicted to glutamine through up-regulation of glutamate pyruvate transaminase 2 (GPT2). A GPT2 inhibitor suppresses in vivo growth of PIK3CA mutant, but not wild-type, CRCs. This study indicates that targeting glutamine may be an effective approach to treat CRCs with PIK3CA mutations.

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          Most cited references2

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          Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer.

          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.
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            Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer

            Cancer cells often require glutamine for growth, thereby distinguishing them from most normal cells. Here we show that PIK3CA mutations reprogram glutamine metabolism by upregulating glutamate pyruvate transaminase 2 (GPT2) in colorectal cancer (CRC) cells, making them more dependent on glutamine. Compared with isogenic wild-type (WT) cells, PIK3CA mutant CRCs convert substantially more glutamine to α-ketoglutarate to replenish the tricarboxylic acid cycle and generate ATP. Mutant p110α upregulates GPT2 gene expression through an AKT-independent, PDK1–RSK2–ATF4 signalling axis. Moreover, aminooxyacetate, which inhibits the enzymatic activity of aminotransferases including GPT2, suppresses xenograft tumour growth of CRCs with PIK3CA mutations, but not with WT PIK3CA. Together, these data establish oncogenic PIK3CA mutations as a cause of glutamine dependency in CRCs and suggest that targeting glutamine metabolism may be an effective approach to treat CRC patients harbouring PIK3CA mutations.
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              Author and article information

              Contributors
              Journal
              Genes Dis
              Genes Dis
              Genes & Diseases
              Chongqing Medical University
              2352-4820
              2352-3042
              10 September 2016
              December 2016
              10 September 2016
              : 3
              : 4
              : 241-243
              Affiliations
              [1]Department of Genetics and Genome Sciences and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
              Author notes
              []Corresponding author. zxw22@ 123456case.edu
              Article
              S2352-3042(16)30037-X
              10.1016/j.gendis.2016.09.001
              6153462
              73dfcb9e-db84-474d-a62d-2057704534ee
              Copyright © 2016, Chongqing Medical University. Production and hosting by Elsevier B.V.

              This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

              History
              : 26 August 2016
              : 3 September 2016
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