Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma.

Adenine / analogs & derivatives Animals Cell Line, Tumor DNA Copy Number Variations / genetics Drug Resistance, Neoplasm / genetics Lymphoma, Mantle-Cell / drug therapy Mice Molecular Targeted Therapy Mutation / genetics Oxidative Phosphorylation / drug effects Piperidines Pyrazoles / pharmacology Pyrimidines / pharmacology Signal Transduction / drug effects Transcriptome / genetics Exome Sequencing

Journal

Science translational medicine
ISSN: 1946-6242
Titre abrégé: Sci Transl Med
Pays: United States
ID NLM: 101505086

Informations de publication

Date de publication:
08 05 2019
Historique:
received: 09 05 2018
revised: 02 11 2018
accepted: 29 03 2019
entrez: 10 5 2019
pubmed: 10 5 2019
medline: 15 7 2020
Statut: ppublish

Résumé

Metabolic reprogramming is linked to cancer cell growth and proliferation, metastasis, and therapeutic resistance in a multitude of cancers. Targeting dysregulated metabolic pathways to overcome resistance, an urgent clinical need in all relapsed/refractory cancers, remains difficult. Through genomic analyses of clinical specimens, we show that metabolic reprogramming toward oxidative phosphorylation (OXPHOS) and glutaminolysis is associated with therapeutic resistance to the Bruton's tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma (MCL), a B cell lymphoma subtype with poor clinical outcomes. Inhibition of OXPHOS with a clinically applicable small molecule, IACS-010759, which targets complex I of the mitochondrial electron transport chain, results in marked growth inhibition in vitro and in vivo in ibrutinib-resistant patient-derived cancer models. This work suggests that targeting metabolic pathways to subvert therapeutic resistance is a clinically viable approach to treat highly refractory malignancies.

Identifiants

DOI: 10.1126/scitranslmed.aau1167 PMID: 31068440
pubmed: 31068440
pii: 11/491/eaau1167
doi: 10.1126/scitranslmed.aau1167
pii:
doi:

Substances chimiques

Piperidines 0
Pyrazoles 0
Pyrimidines 0
ibrutinib 1X70OSD4VX
Adenine JAC85A2161

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

Subventions

Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA202104
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Auteurs

Liang Zhang (L)

Department of Lymphoma and Myeloma, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
ORCID: 0000-0001-9218-828X

Yixin Yao (Y)

Department of Lymphoma and Myeloma, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
ORCID: 0000-0002-8439-6043

Shaojun Zhang (S)

Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
ORCID: 0000-0001-5760-5797

Yang Liu (Y)

Department of Lymphoma and Myeloma, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
ORCID: 0000-0002-1910-8076

Hui Guo (H)

Department of Lymphoma and Myeloma, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Makhdum Ahmed (M)

Department of Lymphoma and Myeloma, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
ORCID: 0000-0002-0772-8710

Taylor Bell (T)

Department of Lymphoma and Myeloma, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
ORCID: 0000-0003-2791-7188

Hui Zhang (H)

Department of Lymphoma and Myeloma, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
ORCID: 0000-0003-1673-2444

Guangchun Han (G)

Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
ORCID: 0000-0001-9277-2507

Elizabeth Lorence (E)

Department of Lymphoma and Myeloma, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
ORCID: 0000-0003-0051-6835

Maria Badillo (M)

Department of Lymphoma and Myeloma, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Shouhao Zhou (S)

Department of Biostatistics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
ORCID: 0000-0002-8124-5047

Yuting Sun (Y)

Institute for Applied Cancer Science and Center for Co-Clinical Trials, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

M Emilia Di Francesco (ME)

Institute for Applied Cancer Science and Center for Co-Clinical Trials, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
ORCID: 0000-0002-5132-1643

Ningping Feng (N)

Institute for Applied Cancer Science and Center for Co-Clinical Trials, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Randy Haun (R)

Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

Renny Lan (R)

Department of Biochemistry and Molecular Biology and Proteomics Core Facility, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
ORCID: 0000-0001-8346-043X

Samuel G Mackintosh (SG)

Department of Biochemistry and Molecular Biology and Proteomics Core Facility, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

Xizeng Mao (X)

Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Xingzhi Song (X)

Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Jianhua Zhang (J)

Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
ORCID: 0000-0001-5412-9860

Lan V Pham (LV)

Department of Hematopathology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Philip L Lorenzi (PL)

Proteomics and Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
ORCID: 0000-0003-0385-7774

Joseph Marszalek (J)

Institute for Applied Cancer Science and Center for Co-Clinical Trials, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
ORCID: 0000-0003-2320-3209

Tim Heffernan (T)

Institute for Applied Cancer Science and Center for Co-Clinical Trials, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
ORCID: 0000-0002-3166-8922

Giulio Draetta (G)

Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Institute for Applied Cancer Science and Center for Co-Clinical Trials, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
ORCID: 0000-0001-5225-9610

Philip Jones (P)

Institute for Applied Cancer Science and Center for Co-Clinical Trials, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
ORCID: 0000-0001-6149-8293

Andrew Futreal (A)

Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
ORCID: 0000-0001-8663-2671

Krystle Nomie (K)

Department of Lymphoma and Myeloma, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Linghua Wang (L)

Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. lwang22@mdanderson.org miwang@mdanderson.org.
ORCID: 0000-0001-9380-0266

Michael Wang (M)

Department of Lymphoma and Myeloma, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. lwang22@mdanderson.org miwang@mdanderson.org.
Department of Stem Cell Transplantation and Cellular Therapy, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
ORCID: 0000-0001-9748-5486

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Classifications MeSH

questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Purines › Adénine › Metabolic reprogramming toward oxidative...
questionsmedicales.fr › Eucaryotes › Animaux › Metabolic reprogramming toward oxidative...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Metabolic reprogramming toward oxidative...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Variation structurale du génome › Variations de nombre de copies de segment d'ADN › Metabolic reprogramming toward oxidative...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance aux médicaments antinéoplasiques › Metabolic reprogramming toward oxidative...
questionsmedicales.fr › Maladies du système immunitaire › Syndromes immunoprolifératifs › Syndromes lymphoprolifératifs › Lymphomes › Lymphome malin non hodgkinien › Lymphome à cellules du manteau › Metabolic reprogramming toward oxidative...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Metabolic reprogramming toward oxidative...
questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Thérapie moléculaire ciblée › Metabolic reprogramming toward oxidative...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Metabolic reprogramming toward oxidative...
questionsmedicales.fr › Métabolisme › Phosphorylation › Phosphorylation oxydative › Metabolic reprogramming toward oxidative...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pipéridines › Metabolic reprogramming toward oxidative...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Azoles › Pyrazoles › Metabolic reprogramming toward oxidative...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyrimidines › Metabolic reprogramming toward oxidative...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Metabolic reprogramming toward oxidative...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Transcriptome › Metabolic reprogramming toward oxidative...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ADN › Séquençage du génome entier › Séquençage de l'exome › Metabolic reprogramming toward oxidative...