Radiotherapy and radio-sensitization in H3K27M -mutated diffuse midline gliomas.

Abstract

H3K27M mutated diffuse midline gliomas (DMGs) are extremely aggressive and the leading cause of cancer-related deaths in pediatric brain tumors with 5-year survival <1%. Radiotherapy is the only established adjuvant treatment of H3K27M DMGs; however, the radio-resistance is commonly observed. We summarized current understandings of the molecular responses of H3K27M DMGs to radiotherapy and provide crucial insights into current advances in radiosensitivity enhancement. Ionizing radiation (IR) can mainly inhibit tumor cell growth by inducing DNA damage regulated by the cell cycle checkpoints and DNA damage repair (DDR) system. In H3K27M DMGs, the aberrant genetic and epigenetic changes, stemness genotype, and epithelial-mesenchymal transition (EMT) disrupt the cell cycle checkpoints and DDR system by altering the associated regulatory signaling pathways, which leads to the development of radio-resistance. The advances in mechanisms of radio-resistance in H3K27M  DMGs promote the potential targets to enhance the sensitivity to radiotherapy.