Polθ Inhibition Enhances Talazoparib Radiosensitization in Homologous Recombination-Proficient Cancer Cells

The PARP1/2 inhibitor talazoparib (BMN673) is an FDA-approved drug used as a monotherapy for treating homologous recombination (HR) compromised tumors. We previously found that talazoparib combined with radiotherapy (RT) also exerts marked radiosensitizing effects on cancer cells with functional HR. Mechanistically, talazoparib modulates ionizing radiation (IR) -induced DNA double-strand break (DSB) repair pathway choice towards error-prone alternative pathways of DSB end-joining (alt-EJ). Here, we investigate whether talazoparib-induced radiosensitization can be further enhanced by inhibiting this enhanced alt-EJ activity in talazoparib treated cells. DNA polymerase theta (Polθ) is a key component of alt-EJ and has recently been reported to suppress the growth of HR-deficient tumors. However, combinations of Polθ inhibition with talazoparib and RT have not been explored. We show that talazoparib-treated cancer cells can be markedly radiosensitized by genetic ablation or pharmacological inhibition of Polθ. Such robust radiosensitization was not observed in cells treated with other clinically used PARP inhibitors such as veliparib, rucaparib, and olaparib. Talazoparib-treated cells show high dependence on alt-EJ owing to CtIP/MRE11 dependent hyper-resection resulting in elevated chromosomal translocation formation by Polθ. Combined talazoparib / Polθ inhibition impairs IR-induced DSB repair, culminating in the formation of chromosome breaks that underpin radiosensitization. Our findings demonstrate that treatment schedules combining talazoparib with Polθ inhibition have the potential to radiosensitize cancer cells during RT.