Targeting Cell Cycle Checkpoint Kinases to Overcome Intrinsic Radioresistance in Brain Tumor Cells

Radiation therapy is an important part of the standard of care treatment of brain tumors. However, the efficacy of radiation therapy is limited by the radioresistance of tumor cells, a phenomenon held responsible for the dismal prognosis of the most aggressive brain tumor types. A promising approach to radiosensitization of tumors is the inhibition of cell cycle checkpoint control responsible for cell cycle progression and the maintenance of genomic integrity. Inhibition of the kinases involved in these control mechanisms can abolish cell cycle checkpoints and DNA damage repair and thus increase the sensitivity of tumor cells to radiation and chemotherapy. Here, we discuss preclinical progress in molecular targeting of ATM, ATR, CHK1, CHK2, and WEE1, checkpoint kinases in the treatment of brain tumors, and review current clinical phase I-II trials.