Polθ Inhibitor (ART558) Demonstrates a Synthetic Lethal Effect with PARP and RAD52 Inhibitors in Glioblastoma Cells
DNA repair proteins have emerged as prominent targets in cancer treatment research. In our studies, we hypothesized that inhibiting DNA polymerase theta (Polθ), in combination with either Poly (ADP-ribose) polymerase 1 (PARP1) or RAD52 inhibitors, as well as the alkylating agent temozolomide (TMZ), would have an anticancer effect on glioblastoma cells (GBM21), while exerting minimal impact on normal human astrocytes (NHA). To evaluate this, we assessed the effects of these compounds on cell viability, apoptosis, proliferation, DNA damage, cell cycle distribution, and gene expression. Our key findings ART558 indicate that Polθ inhibition significantly reduces the viability of glioblastoma cells, induces apoptosis, decreases cell proliferation, and causes DNA damage. Furthermore, the combination of Polθ inhibition with PARP1 or RAD52 inhibitors resulted in an even stronger effect, which was further intensified by the addition of TMZ. Importantly, the impact on normal cells, particularly in terms of cell viability and DNA damage, was considerably lower. In conclusion, we emphasize that the combined inhibition of Polθ with PARP1 or RAD52 presents significant potential for selectively targeting glioblastoma cells, demonstrating a synthetic lethal effect while sparing normal astrocytes.