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

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          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.


          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).


          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.

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          Most cited references 37

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

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            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.
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              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.

                Author and article information

                Clin Transl Med
                Clin Transl Med
                Clinical and Translational Medicine
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                18 January 2017
                18 January 2017
                : 6
                [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
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, 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.

                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
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                © The Author(s) 2017



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