Blog
About

7
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      The antineoplastic drug, trastuzumab, dysregulates metabolism in iPSC-derived cardiomyocytes

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          The targeted ERBB2 therapy, trastuzumab, has had a tremendous impact on management of patients with HER2+ breast cancer, leading to development and increased use of further HER2 targeted therapies. The major clinical side effect is cardiotoxicity but the mechanism is largely unknown. On the basis that gene expression is known to be altered in multiple models of heart failure, we examined differential gene expression of iPSC-derived cardiomyocytes treated at day 11 with the ERBB2 targeted monoclonal antibody, trastuzumab for 48 h and the small molecule tyrosine kinase inhibitor of EGFR and ERBB2.

          Results

          Transcriptome sequencing was performed on four replicates from each group (48 h untreated, 48 h trastuzumab and 48 h lapatinib) and differential gene expression analyses were performed on each treatment group relative to untreated cardiomyocytes. 517 and 1358 genes were differentially expressed, p < 0.05, respectively in cardiomyocytes treated with trastuzumab and lapatinib. Gene ontology analyses revealed in cardiomyocytes treated with trastuzumab, significant down-regulation of genes involved in small molecule metabolism (p = 3.22 × 10 −9) and cholesterol (p = 0.01) and sterol (p = 0.03) processing. We next measured glucose uptake and lactate production in iPSC-derived cardiomyocytes 13 days post-plating, treated with trastuzumab up to 96 h. We observed significantly decreased glucose uptake from the media of iPSC-derived cardiomyocytes treated with trastuzumab as early as 24 h (p = 0.001) and consistently up to 96 h (p = 0.03).

          Conclusions

          Our study suggests dysregulation of cardiac gene expression and metabolism as key elements of ERBB2 signaling that could potentially be early biomarkers of cardiotoxicity.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s40169-016-0133-2) contains supplementary material, which is available to authorized users.

          Related collections

          Most cited references 37

          • Record: found
          • Abstract: not found
          • Article: not found

          Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.

            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941.

            Herceptin (trastuzumab) is the backbone of HER2-directed breast cancer therapy and benefits patients in both the adjuvant and metastatic settings. Here, we describe a mechanism of action for trastuzumab whereby antibody treatment disrupts ligand-independent HER2/HER3 interactions in HER2-amplified cells. The kinetics of dissociation parallels HER3 dephosphorylation and uncoupling from PI3K activity, leading to downregulation of proximal and distal AKT signaling, and correlates with the antiproliferative effects of trastuzumab. A selective and potent PI3K inhibitor, GDC-0941, is highly efficacious both in combination with trastuzumab and in the treatment of trastuzumab-resistant cells and tumors.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes.

              The network for cardiac fuel metabolism contains intricate sets of interacting pathways that result in both ATP-producing and non-ATP-producing end points for each class of energy substrates. The most salient feature of the network is the metabolic flexibility demonstrated in response to various stimuli, including developmental changes and nutritional status. The heart is also capable of remodeling the metabolic pathways in chronic pathophysiological conditions, which results in modulations of myocardial energetics and contractile function. In a quest to understand the complexity of the cardiac metabolic network, pharmacological and genetic tools have been engaged to manipulate cardiac metabolism in a variety of research models. In concert, a host of therapeutic interventions have been tested clinically to target substrate preference, insulin sensitivity, and mitochondrial function. In addition, the contribution of cellular metabolism to growth, survival, and other signaling pathways through the production of metabolic intermediates has been increasingly noted. In this review, we provide an overview of the cardiac metabolic network and highlight alterations observed in cardiac pathologies as well as strategies used as metabolic therapies in heart failure. Lastly, the ability of metabolic derivatives to intersect growth and survival are also discussed.
                Bookmark

                Author and article information

                Contributors
                Necela.brian@mayo.edu
                Axenfeld.bianca@mayo.edu
                Serie.daniel@mayo.edu
                Kachergus.jennifer@mayo.edu
                Perez.edith@mayo.edu
                Thompson.aubrey@mayo.edu
                Norton.nadine@mayo.edu
                Journal
                Clin Transl Med
                Clin Transl Med
                Clinical and Translational Medicine
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                2001-1326
                18 January 2017
                18 January 2017
                2017
                : 6
                Affiliations
                [1 ]ISNI 0000 0004 0443 9942, GRID grid.417467.7, Department of Cancer Biology, , Mayo Clinic, ; Jacksonville, FL USA
                [2 ]ISNI 0000 0004 0443 9942, GRID grid.417467.7, Department of Health Sciences Research, , Mayo Clinic, ; Jacksonville, FL USA
                [3 ]ISNI 0000 0004 0443 9942, GRID grid.417467.7, Department of Hematology Oncology, , Mayo Clinic, ; Jacksonville, FL USA
                Article
                133
                10.1186/s40169-016-0133-2
                5243239
                28101782
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                Funding
                Funded by: Mayo Clinic Transplant and Regenerative Medicine Focused Research Group
                Funded by: The MacKenzie Foundation
                Funded by: The 26.2 with Donna Foundation
                Funded by: Gerstner Career Development Award
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Medicine

                Comments

                Comment on this article