Increased sensitivity to ionizing radiation by targeting the homologous recombination pathway in glioma initiating cells

Abstract

Glioblastoma is deemed the most malignant form of brain tumour, particularly due to its resistance to conventional treatments. A small surviving group of aberrant stem cells termed glioma initiation cells (GICs) that escape surgical debulking are suggested to be the cause of this resistance. Relatively quiescent in nature, GICs are capable of driving tumour recurrence and undergo lineage differentiation. Most importantly, these GICs are resistant to radiotherapy, suggesting that radioresistance contribute to their survival. In a previous study, we demonstrated that GICs had a restricted double strand break (DSB) repair pathway involving predominantly homologous recombination (HR) associated with a lack of functional G1/S checkpoint arrest. This unusual behaviour led to less efficient non-homologous end joining (NHEJ) repair and overall slower DNA DSB repair kinetics. To determine whether specific targeting of the HR pathway with small molecule inhibitors could increase GIC radiosensitivity, we used the Ataxia-telangiectasia mutated inhibitor (ATMi) to ablate HR and the DNA-dependent protein kinase inhibitor (DNA-PKi) to inhibit NHEJ. Pre-treatment with ATMi prior to ionizing radiation (IR) exposure prevented HR-mediated DNA DSB repair as measured by Rad51 foci accumulation. Increased cell death in vitro and improved in vivo animal survival could be observed with combined ATMi and IR treatment. Conversely, DNA-PKi treatment had minimal impact on GICs ability to resolve DNA DSB after IR with only partial reduction in cell survival, confirming the major role of HR. These results provide a mechanistic insight into the predominant form of DNA DSB repair in GICs, which when targeted may be a potential translational approach to increase patient survival.

miR-128 regulates the apoptosis and proliferation of glioma cells by targeting RhoE

“…It is well known that glioma cells have significant proliferation ability and a low apoptosis rate, as well as a powerful resistance to chemotherapy, radiation and biological treatment (13)(14)(15). These characteristics contribute to the malignant growth of tumors and may be a key reason for the recurrence of glioma (16).…”

RAD51 Is a Selective DNA Repair Target to Radiosensitize Glioma Stem Cells

“…Previously, we reported that targeting RAD51 using small interfering RNA-radiosensitized established glioma cell lines, and recent data confirm that targeting HR is more effective at radiosensitizing GSCs than inhibiting the major alternative DSB repair pathway, non-homologous end-joining (NHEJ) (Lim et al., 2014, Short et al., 2011). Inhibition of HR can be achieved through modulating expression, inhibiting nuclear translocation, or preventing DNA binding of RAD51, and small-molecule inhibitors have been developed, including B02 and RI-1.…”

Hyperthermia Sensitizes Glioma Stem-like Cells to Radiation by Inhibiting AKT Signaling

“…Inhibition of DNA repair improves the radiosensitivity of GSCs (27). Hyperthermia is thought to act as a radiosensitizer primarily by interference of DNA damage repair (28).…”