Abstract
Simple SummaryAs 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.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.
Highlights
Accepted: 27 January 2022Brain tumors include primary brain tumors and brain metastases
We focus on primary brain tumors, of which the most common in adults are gliomas arising from glial cells [1]
The application of RT is restricted by the level of tolerance of the normal tissue, the prognosis for the most aggressive brain tumors has remained very poor over the past decades
Summary
Brain tumors include primary brain tumors and brain metastases. In this review, we focus on primary brain tumors, of which the most common in adults are gliomas arising from glial cells [1]. Ionizing radiation induces DNA double-strand breaks (DSBs), single-strand breaks (SSBs), base damage, and abasic sites. In contrast with other forms of oxidative stress, ionizing radiation produces tracks of spatially correlated ionizations, some of which are close enough to cause more serious DNA damage, such as DSBs and complex lesions. Recent reviews have described mechanisms and strategies for targeting DNA repair in brain tumors [10,11]. The present review will target the DNA damage response (DDR) by inhibiting kinases involved in the S and G2/M checkpoints to increase mitotic failure. Before discussing this strategy, we will briefly review the heterogeneity of GBM tumors and the role of glioma stem cells (GSCs) in therapy resistance
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