Eradication of LIG4-deficient glioblastoma cells by the combination of PARP inhibitor and alkylating agent

• DOI: 10.18632/oncotarget.26409
• Publication Date: 2018-12-07T16:34:19Z
• Authors: Monika Toma; Monika Witusik-Pe...; Marzena Szwed; Robert Stawski; Janusz Szemraj; Malgorzata Drzewi...; Margaret Nieborow...; Maciej Radek; Pawel Kolasa; Ksenia Matlawska-...; Tomasz Sliwinski; Tomasz Skorski
• Keywords: Temozolomide; PARP inhibitor; Synthetic Lethality; Veliparib

Cancer cells often accumulate spontaneous and treatment-induced DNA damage i.e. potentially lethal double strand breaks (DSBs). Targeting DSB repair mechanisms with specific inhibitors could sensitize cancer to the toxic effect of DSBs. Current treatment for glioblastoma includes tumor resection followed by radiotherapy and/or temozolomide (TMZ) - an alkylating agent inducing damage. We hypothesize that combination PARP inhibitor (PARPi) TMZ in displaying downregulation genes trigger synthetic lethality. In our study, we observed (BMN673) was able specifically ligase 4 (LIG4)-deprived while normal astrocytes were not affected. LIG4 resulting low effectiveness DNA-PK-mediated non-homologous end-joining (D-NHEJ), which BMN673 resulted accumulation DSBs eradication cells. Restoration expression caused loss sensitivity BMN673+TMZ. conclusion, combined agents can be utilized patients defects D-NHEJ.