Abstract
Cancer cells often accumulate spontaneous and treatment-induced DNA damage i.e. potentially lethal DNA double strand breaks (DSBs). Targeting DSB repair mechanisms with specific inhibitors could potentially sensitize cancer cells to the toxic effect of DSBs. Current treatment for glioblastoma includes tumor resection followed by radiotherapy and/or temozolomide (TMZ) – an alkylating agent inducing DNA damage. We hypothesize that combination of PARP inhibitor (PARPi) with TMZ in glioblastoma cells displaying downregulation of DSB repair genes could trigger synthetic lethality. In our study, we observed that PARP inhibitor (BMN673) was able to specifically sensitize DNA ligase 4 (LIG4)-deprived glioblastoma cells to TMZ while normal astrocytes were not affected. LIG4 downregulation resulting in low effectiveness of DNA-PK–mediated non-homologous end-joining (D-NHEJ), which in combination with BMN673 and TMZ resulted in accumulation of lethal DSBs and specific eradication of glioblastoma cells. Restoration of the LIG4 expression caused loss of sensitivity to BMN673+TMZ. In conclusion, PARP inhibitor combined with DNA damage inducing agents can be utilized in patients with glioblastoma displaying defects in D-NHEJ.
Highlights
Glioblastoma [1] is the most frequent primary brain tumor with very poor survival rate [2]
Expression of genes involved in DNA double strand break (DSB) repair in normal human astrocytes and glioblastoma cells
The subject of our interest were 15 genes involved in DSB repair pathways (BRCA1, BRCA2, PALB2, RAD51B, RAD51C, RAD51D, XRCC2, XRCC3, RAD52 taking part in homologous recombination (HR); ligase 4 (LIG4), DNA-PKcs, XRCC5, XRCC6 in D-non-homologous end-joining (NHEJ); and PARP1, LIG3 in backup NHEJ (B-NHEJ))
Summary
Glioblastoma (grade IV in WHO Classification of Tumors of the Central Nervous System) [1] is the most frequent primary brain tumor with very poor survival rate (median of 14.6 months) [2]. One of the hallmarks of the cancerous cells is genomic instability responsible for accumulation of further genome rearrangements and tumor progression [5]. Development of such abnormalities in primary DNA repair systems results in activation of compensatory DNA repair mechanism, ipso facto, inducing cell “addiction” to the changes it carries. It has been suggested that cancer-specific abnormalities in the functioning of DNA repair systems and pathway redirection events might be responsible for the resistance and survival of cancer cells after exposure to genotoxic stress [6]
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