Radiation therapy (RT) is frequently used as part of the standard of care treatment of the majority of brain tumors. The efficacy of RT is limited by radioresistance and by normal tissue radiation tolerance. This is highlighted in pediatric brain tumors where the use of radiation is limited by the excessive toxicity to the developing brain. For these reasons, radiosensitization of tumor cells would be beneficial. In this review, we focus on radioresistance mechanisms intrinsic to tumor cells. We also evaluate existing approaches to induce radiosensitization and explore future avenues of investigation.

Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiation therapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell cycle arrest after ionizing radiation. Here, we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a specific small molecule inhibitor of MRK, M443, which binds to MRK in an irreversible fashion and inhibits its activity. We found that M443 strongly radio-sensitizes UW228 medulloblastoma cells as well as UI226 patient-derived primary cells, while it does not affect the response to radiation of normal brain cells. M443 also inhibits radiation-induced activation of both p38 and Chk2, two proteins that act downstream of MRK and are involved in DNA damage-induced cell cycle arrest. Importantly, in an animal model of medulloblastoma that employs orthotopic implantation of primary patient-derived UI226 cells in nude mice, M443 in combination with radiation achieved a synergistic increase in survival. We hypothesize that combining radiotherapy with M443 will allow us to lower the radiation dose while maintaining therapeutic efficacy, thereby minimizing radiation-induced side effects.