DNA Damage Response in Glioblastoma

Abstract

Glioblastoma (GBM) is an intrinsically treatment-resistant tumor and has been shown to upregulate DNA damage response (DDR) components after treatment. DNA damage response signaling mediates treatment resistance by promoting cell cycle arrest in order to allow for DNA damage repair and avoid mitotic catastrophe. Therefore, targeting the DDR pathway is an attractive strategy to combat treatment resistance in GBM. In this review, we discuss the different DDR pathways and then summarize the current preclinical evidence for DDR inhibitors in GBM, as well as completed and ongoing clinical trials.

HMGB2 is a biomarker associated with poor prognosis promoting radioresistance in glioma by targeting base excision repair pathway

“…Tumor cells can also repair their own DNA through the above pathway to avoid apoptosis and increase invasiveness. Previous studies have found that glioblastoma contains stem cell-like subsets, showing high expression of DNA damage response factors, resulting in therapeutic resistance and disease recurrence [ 39 ].At present, the clinical trials of DDR inhibitors in gliomas are very popular, and the therapeutic targets include:PARP/ DNA-PK/Chk1/ATM [ 40 ]. However, there is no targeted drugs with clear benefits have been found so far, we speculate that it may be because the specific DDR pathway inhibitors were not selected for treatment based on the corresponding high expression biomarkers.…”

New perspective on DNA response pathway (DDR) in glioblastoma, focus on classic biomarkers and emerging roles of ncRNAs

“…Intact p53 activity is required for efficient cell cycle progression through the G1/S checkpoint, its mutational loss of function is allowing cancer cells to pass the checkpoints with replicating errors and to accumulate DNA damage (Ref. 16). For example, treatment with RT and DNA-PK inhibitor M3814 on p53 mutated cell lines lead to mitotic catastrophe and apoptotic cell death, as the replication mechanism was unable to arrest the cell cycle and repair the induced DNA damage (Ref.…”

“…Thus, there are some limitations regarding the treatment with ATR inhibitors, as they could harm both cancerous and noncancerous cells. At the moment, there are no specific ATR inhibitors clinical trials for GBM, due to their increased toxicity in preclinical studies (Refs 16, 95). Yet, there are ongoing clinical trials that test ATR inhibitors in combination with RT or other chemotherapy: Elimusertib (BAY1895344) with Pembrolizumab for advanced solid tumours (NCT04095273) or Elimusertib with Pembrolizumab and Stereotactic Body Radiation Therapy for recurrent head and neck cancer (NCT04576091) or AZD6738 with Olaparib (AZD2281) for Clear Cell Renal Cell Carcinoma and Advanced Pancreatic Cancer (NCT03682289).…”

“…Also, dysfunction of p53 is influencing the cell response to the G2/M checkpoint, therefore increasing cellular susceptibility to ATR, CHK2 and Wee1 inhibitors (Ref. 16).…”

“…DDR are induced as an adaptive reaction to either single or double-strand breaks (SSB/DSB) of the genomic DNA, which occur as a consequence of the endogenous genomic instability associated with GBM development or as a post-conventional treatment side-effect. The restoration of SSB, which are the most common DNA lesions, is mediated by base excision repair (BER), nucleotide excision repair (NER) and mismatch repair (MMR) mechanisms, while the DSB restoration is mediated by either homologous recombination (HR) or nonhomologous end-joining (NHEJ) mechanisms (Refs 16, 17) One clear example for the use of DDR pathway in GBM therapy are the poly ADP-ribose polymerase (PARP) inhibitors, especially those that target PARP-1. Normally, this enzyme binds to the injured DNA site catalysing the formation of ADP-ribose polymers using NAD + as a substrate and activates the necessary enzymes for BER to be conducted.…”