AI Article Synopsis
- Diffuse midline gliomas (DMG), particularly those with the H3K27M mutation, are a deadly brain cancer characterized by altered metabolism and resistance to radiation therapy.
- Researchers conducted metabolomics on H3K27M DMG cell lines to identify key pathways, focusing on purine metabolism and how it relates to treatment resistance.
- Results indicated that H3K27M cells rely heavily on purine synthesis, but adapt to radiation by increasing purine salvage activity; inhibiting this adaptive response could enhance the effectiveness of treatment.
Article Abstract
Background: 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: 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 and response to and salvage purine synthesis inhibition in combination with RT.
Results: 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 synthesis and lower activity of purine salvage due to decreased expression of the purine salvage enzymes. Inhibition of synthesis radiosensitized DMG-H3K27M cells and . Irradiated H3K27M cells adaptively upregulate purine salvage enzyme expression and pathway activity. Silencing the rate limiting enzyme in purine salvage, hypoxanthine guanine phosphoribosyl transferase (HGPRT) when combined with radiation markedly suppressed DMG-H3K27M tumor growth .
Conclusions: H3K27M expressing cells rely on purine synthesis but adaptively upregulate purine salvage in response to RT. Inhibiting purine salvage may help overcome treatment resistance in DMG-H3K27M tumors.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10543500 | PMC |
| http://dx.doi.org/10.21203/rs.3.rs-3317816/v1 | DOI Listing |
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