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Addressing the DNA Damage Response to Irradiation and PARP1/PARG Inhibitors in Glioblastoma
O'Donnell, Riona Kathleen
O'Donnell, Riona Kathleen
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Abstract
Grade IV glioblastoma (GBM) is a deadly cancer treated by combining chemotherapy (temozolomide, TMZ) with irradiation (IR). GBM recurrence due to TMZ resistance necessitates novel therapies. Some promising drugs are inhibitors targeting poly(ADP-ribose)polymerase-1 (PARP1) and poly(ADP-ribose)glycohydrolase (PARG), proteins that mediate the post- translational modification PARylation and are important in the DNA damage response (DDR). Cancers with mutations in the tumor suppressor phosphate and tensin homolog (PTEN), like certain GBM tumors, display increased sensitivity to these inhibitors. This project investigated the role of PARylation in GBM by examining the presence of PARP1 and PARG in cells resistant to TMZ and determining the cellular outcomes of treatment with PARP1 and PARG inhibitors in combination with IR. The cell lines LN-229 (PTEN-wild type) and U-87MG (PTEN-mutated) were used to characterize the impact of PTEN status on treatment sensitivity. We find that while PARP1 and PARG are not associated with TMZ resistance, inhibitors of PARP1 and PARG can increase sensitivity to IR in specific cellular contexts in function of PTEN status. Consequently, it is important to continue exploring the link between PARylation and PTEN in GBM.
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2022-01-01