Eradication of LIG4-deficient glioblastoma cells by the combination of PARP inhibitor and alkylating agent.
Document Type
Article
Publication Date
12-7-2018
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.
Publication Title
Oncotarget
ISSN
1949-2553
Volume
9
Issue
96
First Page
36867
Last Page
36877
Recommended Citation
Toma, Monika; Monika Witusik-Perkowska; Marzena Szwed; Robert Stawski; Janusz Szemraj; Malgorzata Drzewiecka; Margaret Nieborowska-Skorska; Maciej Radek; Pawel Kolasa; Ksenia Matlawska-Wasowska; Tomasz Sliwinski; and Tomasz Skorski.
"Eradication of LIG4-deficient glioblastoma cells by the combination of PARP inhibitor and alkylating agent.."
Oncotarget
