LAUSR

Simple Summary Approximately 50% of high-grade gliomas (HGG) in children are diffuse midline gliomas (DMGs), which carry the worst prognosis of all HGG, with a 2-year survival of less than 10%. DMGs are characterized by H3K27M mutation, rampant genomic instability, infiltrative growth, and radio-resistance. Recent large-scale profiling studies have identified some of the key molecular drivers underpinning DMG biology and therapeutic resistance. Here, we provide a comprehensive overview of studies that focus on DMG in the context of radio-resistance. We speculate that the aberrant activation of DNA damage response pathway (DDR) represents a druggable vulnerability, which could be leveraged to radio-sensitize DMGs. Abstract Malignant gliomas (MG) are among the most prevalent and lethal primary intrinsic brain tumors. Although radiotherapy (RT) is the most effective nonsurgical therapy, recurrence is universal. Dysregulated DNA damage response pathway (DDR) signaling, rampant genomic instability, and radio-resistance are among the hallmarks of MGs, with current therapies only offering palliation. A subgroup of pediatric high-grade gliomas (pHGG) is characterized by H3K27M mutation, which drives global loss of di- and trimethylation of histone H3K27. Here, we review the most recent literature and discuss the key studies dissecting the molecular biology of H3K27M-mutated gliomas in children. We speculate that the aberrant activation and/or deactivation of some of the key components of DDR may be synthetically lethal to H3K27M mutation and thus can open novel avenues for effective therapeutic interventions for patients suffering from this deadly disease.