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

SIMPLE SUMMARY: As cell cycle checkpoint mechanisms maintain genomic integrity, the inhibition of enzymes involved in these control mechanisms may increase the sensitivity of the cells to DNA damaging treatments. In this review, we summarize the knowledge in the field of brain tumor treatment with radiation therapy and cell cycle checkpoint inhibition via targeting ATM, ATR, CHK1, CHK2, and WEE1 kinases. ABSTRACT: 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.