TORC1/2 kinase inhibition depletes glutathione and synergizes with carboplatin to suppress the growth of MYC-driven medulloblastoma.

Animals Antineoplastic Agents / pharmacology Carboplatin / therapeutic use Cell Proliferation / physiology Cerebellar Neoplasms / drug therapy Female Glutathione / metabolism Humans Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors Mechanistic Target of Rapamycin Complex 2 / antagonists & inhibitors Medulloblastoma / drug therapy Mice Protein Kinase Inhibitors / pharmacology Proto-Oncogene Proteins c-myc / physiology Xenograft Model Antitumor Assays
Apoptosis INK128 Pediatric brain tumor Sapanisertib mTOR

Journal

Cancer letters
ISSN: 1872-7980
Titre abrégé: Cancer Lett
Pays: Ireland
ID NLM: 7600053

Informations de publication

Date de publication:
28 04 2021
Historique:
received: 01 08 2020
revised: 25 01 2021
accepted: 02 02 2021
pubmed: 12 2 2021
medline: 15 9 2021
entrez: 11 2 2021
Statut: ppublish

Résumé

Medulloblastoma is the most common malignant pediatric brain tumor. Tumors having high levels of c-MYC have the worst clinical prognosis, with only a minority of patients surviving. To address this unmet clinical need, we generated a human neural stem cell model of medulloblastoma that recapitulated the most aggressive subtype phenotypically and by mRNA expression profiling. An in silico analysis of these cells identified mTOR inhibitors as potential therapeutic agents. We hypothesized that the orally bioavailable TORC1/2 kinase inhibitor TAK228 would have activity against MYC-driven medulloblastoma. TAK228 inhibited mTORC1/2, decreased cell growth and caused apoptosis in high-MYC medulloblastoma cell lines. Comprehensive metabolic profiling of medulloblastoma orthotopic xenografts showed upregulation of glutathione compared to matched normal brain. TAK228 suppressed glutathione production. Because glutathione is required to detoxify platinum-containing chemotherapy, we hypothesized that TAK228 would cooperate with carboplatin in medulloblastoma. TAK228 synergized with carboplatin to inhibit cell growth and induce apoptosis and extended survival in orthotopic xenografts of high-MYC medulloblastoma. Brain-penetrant TORC1/2 inhibitors and carboplatin may be an effective combination therapy for high-risk medulloblastoma.

Identifiants

DOI: 10.1016/j.canlet.2021.02.001 PMID: 33571541 PMC: PMC9195565
pubmed: 33571541
pii: S0304-3835(21)00066-5
doi: 10.1016/j.canlet.2021.02.001
pmc: PMC9195565
mid: NIHMS1809193
pii:
doi:

Substances chimiques

Antineoplastic Agents 0
Protein Kinase Inhibitors 0
Proto-Oncogene Proteins c-myc 0
Carboplatin BG3F62OND5
Mechanistic Target of Rapamycin Complex 1 EC 2.7.11.1
Mechanistic Target of Rapamycin Complex 2 EC 2.7.11.1
Glutathione GAN16C9B8O

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

137-145

Subventions

Organisme : NIGMS NIH HHS
ID : R01 GM074024
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA006973
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA194107
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA184898
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA220341
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA209891
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA217885
Pays : United States

Informations de copyright

Copyright © 2021 Elsevier B.V. All rights reserved.

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Auteurs

Rachael E Maynard (RE)

Division of Pediatric Oncology, Department of Oncology, USA.

Brad Poore (B)

Division of Pediatric Oncology, Department of Oncology, USA; Pathobiology Graduate Program, USA.

Allison R Hanaford (AR)

Division of Pediatric Oncology, Department of Oncology, USA; Pathobiology Graduate Program, USA.

Khoa Pham (K)

Division of Neuropathology, Department of Pathology, USA.

Madison James (M)

Pathobiology Graduate Program, USA.

Jesse Alt (J)

Johns Hopkins Drug Discovery, USA.

Youngran Park (Y)

Division of Pediatric Oncology, Department of Oncology, USA.

Barbara S Slusher (BS)

Johns Hopkins Drug Discovery, USA; Department of Neurology, USA.

Pablo Tamayo (P)

Moores Cancer Center, University of California San Diego, La Jolla, CA, USA; Center for Novel Therapeutics, University of California San Diego, La Jolla, CA, USA; Department of Medicine, University of California San Diego, La Jolla, CA, USA.

Jill Mesirov (J)

Moores Cancer Center, University of California San Diego, La Jolla, CA, USA; Department of Medicine, University of California San Diego, La Jolla, CA, USA.

Tenley C Archer (TC)

Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Cambridge, MA, USA.

Scott L Pomeroy (SL)

Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Cambridge, MA, USA.

Charles G Eberhart (CG)

Division of Neuropathology, Department of Pathology, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, USA.

Eric H Raabe (EH)

Division of Pediatric Oncology, Department of Oncology, USA; Division of Neuropathology, Department of Pathology, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, USA. Electronic address: eraabe2@jhmi.edu.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › TORC1/2 kinase inhibition depletes glutathione...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › TORC1/2 kinase inhibition depletes glutathione...
questionsmedicales.fr › Composés chimiques organiques › Complexes de coordination › Carboplatine › TORC1/2 kinase inhibition depletes glutathione...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › TORC1/2 kinase inhibition depletes glutathione...
questionsmedicales.fr › Maladies du système nerveux › Tumeurs du système nerveux › Tumeurs du système nerveux central › Tumeurs du cerveau › Tumeurs sous-tentorielles › Tumeurs du cervelet › TORC1/2 kinase inhibition depletes glutathione...
questionsmedicales.fr › Acides aminés, peptides et protéines › Peptides › Oligopeptides › Glutathion › TORC1/2 kinase inhibition depletes glutathione...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › TORC1/2 kinase inhibition depletes glutathione...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Sérine-thréonine kinases TOR › Complexe-1 cible mécanistique de la rapamycine › TORC1/2 kinase inhibition depletes glutathione...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Sérine-thréonine kinases TOR › Complexe-2 cible mécanistique de la rapamycine › TORC1/2 kinase inhibition depletes glutathione...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu nerveux › Tumeurs neuroectodermiques › Tumeurs neuroépitheliales › Tumeurs neuroectodermiques primitives › Médulloblastome › TORC1/2 kinase inhibition depletes glutathione...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › TORC1/2 kinase inhibition depletes glutathione...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › TORC1/2 kinase inhibition depletes glutathione...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif basique hélice-boucle-hélice › Protéines proto-oncogènes c-myc › TORC1/2 kinase inhibition depletes glutathione...
questionsmedicales.fr › Techniques d'investigation › Transplantation tumorale › Tests d'activité antitumorale sur modèle de xénogreffe › TORC1/2 kinase inhibition depletes glutathione...