Glioblastoma multiforme (GBM) is notoriously resistant to treatment. Therefore, new treatment strategies are urgently needed. ATM elicits the DNA damage response (DDR), which confers cellular radioresistance; thus, targeting the DDR with an ATM inhibitior (ATMi) is very attractive. Herein, we show that dynamic ATM
kinase inhibition in the nanomolar range results in potent radiosensitization of human
glioma cells, inhibits growth and does not conflict with
temozolomide (TMZ) treatment. The second generation ATMi analog
KU-60019 provided quick, reversible and complete inhibition of the DDR at sub-micromolar concentrations in human
glioblastoma cells.
KU-60019 inhibited the phosphorylation of the major DNA damage effectors p53, H2AX and KAP1 as well as AKT. Colony-forming radiosurvival showed that continuous exposure to nanomolar concentrations of
KU-60019 effectively radiosensitized
glioblastoma cell lines. When cells were co-treated with
KU-60019 and TMZ, a slight increase in radiation-induced cell killing was noted, although TMZ alone was unable to radiosensitize these cells. In addition, without radiation,
KU-60019 with or without TMZ reduced
glioma cell growth but had no significant effect on the survival of human embryonic stem cell (hESC)-derived astrocytes. Altogether, transient inhibition of the ATM
kinase provides a promising strategy for radiosensitizing GBM in combination with standard treatment. In addition, without radiation,
KU-60019 limits growth of
glioma cells in co-culture with human astrocytes that seem unaffected by the same treatment. Thus, inter-fraction growth inhibition could perhaps be achieved in vivo with minor adverse effects to the brain.