Human-Induced Pluripotent Stem Cell Model of Trastuzumab-Induced Cardiac Dysfunction in Patients With Breast Cancer.

AMP-Activated Protein Kinases / metabolism Antineoplastic Agents, Immunological / toxicity Breast Neoplasms / drug therapy Calcium Signaling / drug effects Cardiotoxicity Case-Control Studies Cell Line Energy Metabolism / drug effects Female Heart Diseases / chemically induced Humans Induced Pluripotent Stem Cells / drug effects Myocardial Contraction / drug effects Phenotype Risk Factors Transcriptome / drug effects Trastuzumab / toxicity
cardiotoxicity heart failure

Journal

Circulation
ISSN: 1524-4539
Titre abrégé: Circulation
Pays: United States
ID NLM: 0147763

Informations de publication

Date de publication:
21 05 2019
Historique:
pubmed: 15 3 2019
medline: 3 3 2020
entrez: 15 3 2019
Statut: ppublish

Résumé

Molecular targeted chemotherapies have been shown to significantly improve the outcomes of patients who have cancer, but they often cause cardiovascular side effects that limit their use and impair patients' quality of life. Cardiac dysfunction induced by these therapies, especially trastuzumab, shows a distinct cardiotoxic clinical phenotype in comparison to the cardiotoxicity induced by conventional chemotherapies. We used the human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) platform to determine the underlying cellular mechanisms in trastuzumab-induced cardiac dysfunction. We assessed the effects of trastuzumab on structural and functional properties in iPSC-CMs from healthy individuals and performed RNA-sequencing to further examine the effect of trastuzumab on iPSC-CMs. We also generated human induced pluripotent stem cells from patients receiving trastuzumab and examined whether patients' phenotype could be recapitulated in vitro by using patient-specific iPSC-CMs. We found that clinically relevant doses of trastuzumab significantly impaired the contractile and calcium-handling properties of iPSC-CMs without inducing cardiomyocyte death or sarcomeric disorganization. RNA-sequencing and subsequent functional analysis revealed mitochondrial dysfunction and altered the cardiac energy metabolism pathway as primary causes of trastuzumab-induced cardiotoxic phenotype. Human iPSC-CMs generated from patients who received trastuzumab and experienced severe cardiac dysfunction were more vulnerable to trastuzumab treatment than iPSC-CMs generated from patients who did not experience cardiac dysfunction following trastuzumab therapy. It is important to note that metabolic modulation with AMP-activated protein kinase activators could avert the adverse effects induced by trastuzumab. Our results indicate that alterations in cellular metabolic pathways in cardiomyocytes could be a key mechanism underlying the development of cardiac dysfunction following trastuzumab therapy; therefore, targeting the altered metabolism may be a promising therapeutic approach for trastuzumab-induced cardiac dysfunction.

Sections du résumé

BACKGROUND
Molecular targeted chemotherapies have been shown to significantly improve the outcomes of patients who have cancer, but they often cause cardiovascular side effects that limit their use and impair patients' quality of life. Cardiac dysfunction induced by these therapies, especially trastuzumab, shows a distinct cardiotoxic clinical phenotype in comparison to the cardiotoxicity induced by conventional chemotherapies.
METHODS
We used the human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) platform to determine the underlying cellular mechanisms in trastuzumab-induced cardiac dysfunction. We assessed the effects of trastuzumab on structural and functional properties in iPSC-CMs from healthy individuals and performed RNA-sequencing to further examine the effect of trastuzumab on iPSC-CMs. We also generated human induced pluripotent stem cells from patients receiving trastuzumab and examined whether patients' phenotype could be recapitulated in vitro by using patient-specific iPSC-CMs.
RESULTS
We found that clinically relevant doses of trastuzumab significantly impaired the contractile and calcium-handling properties of iPSC-CMs without inducing cardiomyocyte death or sarcomeric disorganization. RNA-sequencing and subsequent functional analysis revealed mitochondrial dysfunction and altered the cardiac energy metabolism pathway as primary causes of trastuzumab-induced cardiotoxic phenotype. Human iPSC-CMs generated from patients who received trastuzumab and experienced severe cardiac dysfunction were more vulnerable to trastuzumab treatment than iPSC-CMs generated from patients who did not experience cardiac dysfunction following trastuzumab therapy. It is important to note that metabolic modulation with AMP-activated protein kinase activators could avert the adverse effects induced by trastuzumab.
CONCLUSIONS
Our results indicate that alterations in cellular metabolic pathways in cardiomyocytes could be a key mechanism underlying the development of cardiac dysfunction following trastuzumab therapy; therefore, targeting the altered metabolism may be a promising therapeutic approach for trastuzumab-induced cardiac dysfunction.

Identifiants

DOI: 10.1161/CIRCULATIONAHA.118.037357 PMID: 30866650 PMC: PMC6528817
pubmed: 30866650
doi: 10.1161/CIRCULATIONAHA.118.037357
pmc: PMC6528817
mid: NIHMS1525396
doi:

Substances chimiques

Antineoplastic Agents, Immunological 0
AMP-Activated Protein Kinases EC 2.7.11.31
Trastuzumab P188ANX8CK

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2451-2465

Subventions

Organisme : NHLBI NIH HHS
ID : P01 HL141084
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141851
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL123968
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL128170
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL132875
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL094274
Pays : United States
Organisme : NHLBI NIH HHS
ID : K01 HL135455
Pays : United States

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Auteurs

Tomoya Kitani (T)

Stanford Cardiovascular Institute, CA (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., R.M.W., N.S., J.C.W.).
Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., N.S., J.C.W.).
Department of Medicine, Division of Cardiology (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., R.M.W., N.S., J.C.W.), Stanford University School of Medicine, CA.

Sang-Ging Ong (SG)

Departments of Pharmacology and Medicine, University of Illinois College of Medicine, Chicago (S.-G.P).

Chi Keung Lam (CK)

Stanford Cardiovascular Institute, CA (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., R.M.W., N.S., J.C.W.).
Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., N.S., J.C.W.).
Department of Medicine, Division of Cardiology (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., R.M.W., N.S., J.C.W.), Stanford University School of Medicine, CA.

June-Wha Rhee (JW)

Stanford Cardiovascular Institute, CA (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., R.M.W., N.S., J.C.W.).
Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., N.S., J.C.W.).
Department of Medicine, Division of Cardiology (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., R.M.W., N.S., J.C.W.), Stanford University School of Medicine, CA.

Joe Z Zhang (JZ)

Stanford Cardiovascular Institute, CA (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., R.M.W., N.S., J.C.W.).
Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., N.S., J.C.W.).
Department of Medicine, Division of Cardiology (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., R.M.W., N.S., J.C.W.), Stanford University School of Medicine, CA.

Angelos Oikonomopoulos (A)

Stanford Cardiovascular Institute, CA (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., R.M.W., N.S., J.C.W.).
Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., N.S., J.C.W.).
Department of Medicine, Division of Cardiology (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., R.M.W., N.S., J.C.W.), Stanford University School of Medicine, CA.

Ning Ma (N)

Stanford Cardiovascular Institute, CA (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., R.M.W., N.S., J.C.W.).
Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., N.S., J.C.W.).
Department of Medicine, Division of Cardiology (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., R.M.W., N.S., J.C.W.), Stanford University School of Medicine, CA.

Lei Tian (L)

Stanford Cardiovascular Institute, CA (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., R.M.W., N.S., J.C.W.).
Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., N.S., J.C.W.).
Department of Medicine, Division of Cardiology (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., R.M.W., N.S., J.C.W.), Stanford University School of Medicine, CA.

Jaecheol Lee (J)

School of Pharmacy, Sungkyunkwan University, Suwon, Korea (J.L.).

Melinda L Telli (ML)

Division of Oncology (M.L.T.), Stanford University School of Medicine, CA.

Ronald M Witteles (RM)

Stanford Cardiovascular Institute, CA (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., R.M.W., N.S., J.C.W.).
Department of Medicine, Division of Cardiology (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., R.M.W., N.S., J.C.W.), Stanford University School of Medicine, CA.

Arun Sharma (A)

Department of Genetics, Harvard Medical School, Boston, MA (A.S.).

Nazish Sayed (N)

Stanford Cardiovascular Institute, CA (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., R.M.W., N.S., J.C.W.).
Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., N.S., J.C.W.).
Department of Medicine, Division of Cardiology (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., R.M.W., N.S., J.C.W.), Stanford University School of Medicine, CA.

Joseph C Wu (JC)

Stanford Cardiovascular Institute, CA (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., R.M.W., N.S., J.C.W.).
Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., N.S., J.C.W.).
Stanford Cancer Institute, CA (J.C.W.).
Department of Medicine, Division of Cardiology (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., R.M.W., N.S., J.C.W.), Stanford University School of Medicine, CA.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › AMP-Activated Protein Kinases › Human-Induced Pluripotent Stem Cell Model of...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Antinéoplasiques immunologiques › Human-Induced Pluripotent Stem Cell Model of...
questionsmedicales.fr › Maladies de la peau et du tissu conjonctif › Maladies de la peau › Maladies du sein › Tumeurs du sein › Human-Induced Pluripotent Stem Cell Model of...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Systèmes de seconds messagers › Signalisation calcique › Human-Induced Pluripotent Stem Cell Model of...
questionsmedicales.fr › Phénomènes physiques › Rayonnement › Cardiotoxicité › Human-Induced Pluripotent Stem Cell Model of...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études cas-témoins › Human-Induced Pluripotent Stem Cell Model of...
questionsmedicales.fr › Cellules › Cellules cultivées › Lignée cellulaire › Human-Induced Pluripotent Stem Cell Model of...
questionsmedicales.fr › Métabolisme › Métabolisme énergétique › Human-Induced Pluripotent Stem Cell Model of...
questionsmedicales.fr › Maladies cardiovasculaires › Cardiopathies › Human-Induced Pluripotent Stem Cell Model of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Human-Induced Pluripotent Stem Cell Model of...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches pluripotentes › Cellules souches pluripotentes induites › Human-Induced Pluripotent Stem Cell Model of...
questionsmedicales.fr › Phénomènes physiologiques de l'appareil locomoteur et du système nerveux › Phénomènes physiologiques du système locomoteur › Contraction musculaire › Contraction myocardique › Human-Induced Pluripotent Stem Cell Model of...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Human-Induced Pluripotent Stem Cell Model of...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Probabilité › Risque › Facteurs de risque › Human-Induced Pluripotent Stem Cell Model of...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Transcriptome › Human-Induced Pluripotent Stem Cell Model of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Anticorps monoclonaux › Anticorps monoclonaux humanisés › Trastuzumab › Human-Induced Pluripotent Stem Cell Model of...