Olaparib Enhances the Efficacy of Third-Generation Oncolytic Adenoviruses Against Glioblastoma by Modulating DNA Damage Response and p66shc-Induced Apoptosis

Aims: Patients with glioblastoma multiforme (GBM) do not benefit from current Cancer treatments, and their prognosis is dismal. This study aimed to investigate the potential synergistic effects of TS-2021, a third-generation oncolytic adenovirus, combined with the PARP Inhibitor olaparib in GBM.

Methods: TS-2021's impact on p66shc-induced Apoptosis, DNA damage response, and poly (ADP-ribose) polymerase (PARP) activation was evaluated in GBM cells. The synergistic effect of TS-2021 and olaparib was examined in GBM cell lines and an immunocompetent mouse model of GBM. Mechanistic studies focused on the role of p66shc phosphorylation in the observed effects.

Results: TS-2021 triggered p66shc-induced Apoptosis, DNA damage response, and PARP activation. The combination of TS-2021 and olaparib synergistically increased cell Apoptosis and DNA damage and reduced PARP expression compared to monotherapy. Olaparib promoted TS-2021 replication and release in GBM cells. Mechanistically, olaparib combined with TS-2021 upregulated p66shc phosphorylation, enhancing tumor cell Apoptosis. In vivo, the combination therapy inhibited tumor growth and prolonged survival, confirming the synergistic effect.

Conclusion: This study is the first to suggest that TS-2021 sensitizes GBM cells with wild-type BRCA1/2 to olaparib. The combination of TS-2021 and olaparib shows a synergistic therapeutic effect against GBM, providing a promising treatment strategy.

DNA damage; PARP; apoptosis; glioblastoma; oncolytic adenovirus; p66shc.