%0 Journal Article
%A Lin, X.
%A Soni, A.
%A Hessenow, R.
%A Stuschke, M.
%A Iliakis, G.
%T Robust Radiosensitization by Combined Treatment of Cancer Cells with Talazoparib and Polθ Inhibitors.
%J International journal of radiation oncology, biology, physics
%V 117
%N 2S
%@ 0360-3016
%C Amsterdam [u.a.]
%I Elsevier Science
%M DKFZ-2023-01985
%P e245
%D 2023
%X The PARP inhibitor talazoparib is synthetically lethal with HR-defective tumors and functions as a potent radiosensitizer specifically of cancer cells. Talazoparib exerts this unique radiosensitizing property by shifting ionizing radiation (IR)-induced DNA double strand break (DSB) repair towards error-prone alternative end-joining (alt-EJ). DNA polymerase theta (Polθ, encoded by POLQ) is a key component of alt-EJ. Here, we tested the hypothesis that inhibition of alt-EJ with Polθ ablation or using specific small molecule inhibitors can further increase talazoparib-induced radiosensitization.U2OS, A549, and their corresponding POLQ ablated/mutant cell lines were treated with talazoparib and/or Polθ inhibitors ART558/novobiocin prior to irradiation. siRNAs against CtIP, MRE11, EXO1; and a specific inhibitor of DNA2 were employed to suppress DNA end resection. Radiosensitization was assessed by clonogenic survival. Olaparib, rucaparib, and veliparib were also tested under similar conditions. DSB repair and end resection were measured by scoring γH2AX and RPA nuclear foci, respectively. Chromosomal abnormalities were assessed using G2-specific cytogenetics analysis.Genetic ablation or pharmacological inhibition of Polθ robustly enhanced talazoparib mediated radiosensitization by ∼40-70
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:37784961
%R 10.1016/j.ijrobp.2023.06.1179
%U https://inrepo02.dkfz.de/record/284396