Adaptive rewiring of purine metabolism promotes treatment resistance in H3K27M-mutant diffuse midline glioma.
Diffuse midline glioma
H3K27M
Radiation therapy resistance
purine metabolism
Journal
Research square
Titre abrégé: Res Sq
Pays: United States
ID NLM: 101768035
Informations de publication
Date de publication:
11 Sep 2023
11 Sep 2023
Historique:
pubmed:
4
10
2023
medline:
4
10
2023
entrez:
4
10
2023
Statut:
epublish
Résumé
Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are a fatal form of brain cancer. These tumors often carry a driver mutation on histone H3 converting lysine 27 to methionine (H3K27M). DMG-H3K27M are characterized by altered metabolism and resistance to standard of care radiation (RT), but how the H3K27M mediates the metabolic response to radiation and consequent treatment resistance is uncertain. We performed metabolomics on irradiated and untreated H3K27M isogenic DMG cell lines and observed an H3K27M-specific enrichment for purine synthesis pathways. We profiled the expression of purine synthesis enzymes in publicly available patient data and in our models, quantified purine synthetic flux using stable isotope tracing, and characterized the DMG-H3K27M cells activate purine metabolism in an H3K27M-specific fashion. In the absence of genotoxic treatment, H3K27M-expressing cells have higher relative activity of H3K27M expressing cells rely on
Sections du résumé
Background
UNASSIGNED
Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are a fatal form of brain cancer. These tumors often carry a driver mutation on histone H3 converting lysine 27 to methionine (H3K27M). DMG-H3K27M are characterized by altered metabolism and resistance to standard of care radiation (RT), but how the H3K27M mediates the metabolic response to radiation and consequent treatment resistance is uncertain.
Methods
UNASSIGNED
We performed metabolomics on irradiated and untreated H3K27M isogenic DMG cell lines and observed an H3K27M-specific enrichment for purine synthesis pathways. We profiled the expression of purine synthesis enzymes in publicly available patient data and in our models, quantified purine synthetic flux using stable isotope tracing, and characterized the
Results
UNASSIGNED
DMG-H3K27M cells activate purine metabolism in an H3K27M-specific fashion. In the absence of genotoxic treatment, H3K27M-expressing cells have higher relative activity of
Conclusions
UNASSIGNED
H3K27M expressing cells rely on
Identifiants
pubmed: 37790517
doi: 10.21203/rs.3.rs-3317816/v1
pmc: PMC10543500
pii:
doi:
Types de publication
Preprint
Langues
eng
Déclaration de conflit d'intérêts
Declarations Competing interests CAL is a member of the Editorial Board of Cancer & Metabolism, and has received consulting fees from Astellas Pharmaceuticals, Odyssey Therapeutics, and T-Knife Therapeutics, and is an inventor on patents pertaining to KRAS-regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting the GOT1-pathway as a therapeutic approach (US patent 2015126580-A1, 05/07/2015; US patent 20190136238, 05/09/2019; international patent WO2013177426-A2, 04/23/2015). DRW has received consulting fees from Agios Pharmaceuticals and Innocrin Pharmaceuticals and is an inventor on patents pertaining to the treatment of patients with brain tumors (U.S. Provisional Patent Application 63/416,146, U.S. Provisional Patent Application 62/744,342, U.S. Provisional Patent Applicant 62/724,337).