The DNA-PK Inhibitor VX-984 Enhances the Radiosensitivity of Glioblastoma Cells Grown In Vitro and as Orthotopic Xenografts

Abstract

Radiotherapy is a primary treatment modality for glioblastomas (GBM). Because DNA-PKcs is a critical factor in the repair of radiation-induced double strand breaks (DSB), this study evaluated the potential of VX-984, a new DNA-PKcs inhibitor, to enhance the radiosensitivity of GBM cells. Treatment of the established GBM cell line U251 and the GBM stem-like cell (GSC) line NSC11 with VX-984 under conditions resulted in a concentration-dependent inhibition of radiation-induced DNA-PKcs phosphorylation. In a similar concentration-dependent manner, VX-984 treatment enhanced the radiosensitivity of each GBM cell line as defined by clonogenic analysis. As determined by γH2AX expression and neutral comet analyses, VX-984 inhibited the repair of radiation-induced DNA double-strand break in U251 and NSC11 GBM cells, suggesting that the VX-984-induced radiosensitization is mediated by an inhibition of DNA repair. Extending these results to an model, treatment of mice with VX-984 inhibited radiation-induced DNA-PKcs phosphorylation in orthotopic brain tumor xenografts, indicating that this compound crosses the blood-brain tumor barrier at sufficient concentrations. For mice bearing U251 or NSC11 brain tumors, VX-984 treatment alone had no significant effect on overall survival; radiation alone increased survival. The survival of mice receiving the combination protocol was significantly increased as compared with control and as compared with radiation alone. These results indicate that VX-984 enhances the radiosensitivity of brain tumor xenografts and suggest that it may be of benefit in the therapeutic management of GBM. .

Radiation resistance in head and neck squamous cell carcinoma: dire need for an appropriate sensitizer

“…More recently, a selective inhibitor of NHEJ, VX-984, that preferentially affects transformed cells was described [85]. Studies in glioblastoma cell lines and tumor-bearing mice showed that VX-984 enhances radiosensitivity of brain tumors [86]. Notably, VX-984 dose dependently inhibited radiation-induced DNA-PKcs phosphorylation and attenuated clonogenic survival [86].…”

“…Studies in glioblastoma cell lines and tumor-bearing mice showed that VX-984 enhances radiosensitivity of brain tumors [86]. Notably, VX-984 dose dependently inhibited radiation-induced DNA-PKcs phosphorylation and attenuated clonogenic survival [86]. The safety and tolerability of VXλ84 in combination with chemotherapy was assessed in participants with solid tumors in clinical trial NCT02644278.…”

Sensitization of Cancer Cells to Radiation and Topoisomerase I Inhibitor Camptothecin Using Inhibitors of PARP and Other Signaling Molecules

“…Thus, repair pathway modulation is a feasible strategy for sensitization to radiotherapy. This idea is further supported by the observation that inhibition of DNA-PK, which inhibits NHEJ, also increases the cytotoxicity of radiation [ 57 , 58 ].…”

“…DNA-dependent protein kinase (DNA-PK) and PARP inhibitors also increase the cytotoxicity of radiation [ 17 , 57 , 58 , 59 , 60 ]. In the presence of PARP inhibitor, damage checkpoint activation in response to radiation exposure is significantly elevated [ 61 ], leading to efficient induction of cancer cell death through apoptosis.…”

Druggable binding sites in the multicomponent assemblies that characterise DNA double-strand-break repair through non-homologous end joining

“…Furthermore, several compounds display mixed activity against DNA-PK, including caffeine [ 72 ], vanillin [ 45 ], and two compounds that are currently in clinical development and act against mTOR and DNA-PK, LY3023414 and CC-15 [ 58 , 59 ]. Newer generation specific DNA-PK compounds include VX-984 and M3814 that are now in clinical development [ 57 , 60 , 61 ]. Preliminary results indicate that VX-984 enhances radio-sensitivity of brain tumour xenografts and could help in management of glioblastoma cells [ 57 ].…”