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

Abstract

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

Adaptation of human iPSC-derived cardiomyocytes to tyrosine kinase inhibitors reduces acute cardiotoxicity via metabolic reprogramming

“…Lapatinib is also known to cause widespread dysregulation of cholesterol biosynthetic enzymes (Necela et al, 2017), as observed here for hiPSC-CMs. We also find that many cell cycle genes are downregulated when hiPSC-CMs are exposed to TKIs.…”

Concise Review: Precision Matchmaking: Induced Pluripotent Stem Cells Meet Cardio-Oncology

“…Compared with animal models, hiPSC‐CMs are more representative of human cardiac physiology in terms of ion channel expression, heart rate, and myofilament composition . Several studies exploring the cardiotoxicity of different chemotherapy agents using stem cell models have been described in the past few years (summarized in Table ).…”

“…A recent study demonstrated that trastuzumab induces cardiotoxicity in hiPSC‐CMs that was dependent on the activation of the erythroblastic oncogene B2/B4 (ErbB2/B4) by either neuregulin (NRG‐1) or heparin‐binding epidermal growth factor, suggesting that trastuzumab is blocking the cardioprotective effects of the ErbB2/4 pathway . In contrast, two other studies showed that trastuzumab‐mediated cardiotoxicity on hiPSC‐CMs is independent of the ErbB2/B4 pathway activation , highlighting the need to develop standardized cell culture conditions to improve the validity of hiPSC‐CMs in trastuzumab‐toxicity screening. More recently, the potential cardiotoxic effects of pertuzumab and trastuzumab‐emtansine (TDM1), a novel antibody–drug conjugate targeting the ErbB2 receptor were tested in the hiPSC‐CMs .…”

Monoclonal antibody-based therapeutics, targeting the epidermal growth factor receptor family: from herceptin to Pan HER

“…It also inhibits HER2 shedding and metalloproteinase activity by decrease PTEN phosphorylation or AKT de‐phosphorylation to induce tumour cells death . Cardiotoxicity is a major reported side effect in trastuzumab‐treated patients and in some cases led to stop the antibody administration …”

“…[79] Cardiotoxicity is a major reported side effect in trastuzumab-treated patients and in some cases led to stop the antibody administration. [82,83] Pertuzumab (PERJETA)…”