Talazoparib enhances resection at DSBs and renders HR-proficient cancer cells susceptible to Polθ inhibition.

Autor: Lin X; Division of Experimental Radiation Biology, Department of Radiation Therapy, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany; Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany., Soni A; Division of Experimental Radiation Biology, Department of Radiation Therapy, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany; Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany. Electronic address: aashish.soni@uk-essen.de., Hessenow R; West German Proton Therapy Center Essen (WPE), University of Duisburg-Essen, 45147, Essen, Germany., Sun Y; Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany; West German Proton Therapy Center Essen (WPE), University of Duisburg-Essen, 45147, Essen, Germany., Mladenov E; Division of Experimental Radiation Biology, Department of Radiation Therapy, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany; Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany., Guberina M; Department of Radiation Therapy, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45147, Essen, Germany; German Cancer Consortium (DKTK), Partner Site University Hospital Essen, German Cancer Research Center (DKFZ), 45147, Essen, Germany., Stuschke M; Division of Experimental Radiation Biology, Department of Radiation Therapy, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany; Department of Radiation Therapy, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45147, Essen, Germany; German Cancer Consortium (DKTK), Partner Site University Hospital Essen, German Cancer Research Center (DKFZ), 45147, Essen, Germany., Iliakis G; Division of Experimental Radiation Biology, Department of Radiation Therapy, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany; Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany. Electronic address: georg.iliakis@uk-essen.de.
Jazyk: angličtina
Zdroj: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology [Radiother Oncol] 2024 Nov; Vol. 200, pp. 110475. Date of Electronic Publication: 2024 Aug 13.
DOI: 10.1016/j.radonc.2024.110475
Abstrakt: Background and Purpose: The PARP inhibitor (PARPi), Talazoparib (BMN673), effectively and specifically radiosensitizes cancer cells. Radiosensitization is mediated by a shift in the repair of ionizing radiation (IR)-induced DNA double-strand breaks (DSBs) toward PARP1-independent, alternative end-joining (alt-EJ). DNA polymerase theta (Polθ) is a key component of this PARP1-independent alt-EJ pathway and we show here that its inhibition can further radiosensitize talazoparib-treated cells. The purpose of the present work is to explore mechanisms and dynamics underpinning enhanced talazoparib radiosensitization by Polθ inhibitors in HR-proficient cancer cells.
Methods and Materials: Radiosensitization to PARPis, talazoparib, olaparib, rucaparib and veliparib was assessed by clonogenic survival. Polθ-proficient and -deficient cells were treated with PARPis and/or with the Polθ inhibitors ART558 or novobiocin. The role of DNA end-resection was studied by down-regulating CtIP and MRE11 expression using siRNAs. DSB repair was assessed by scoring γH2AX foci. The formation of chromosomal abnormalities was assessed as evidence of alt-EJ function using G 2 -specific cytogenetic analysis.
Results: Talazoparib exerted pronounced radiosensitization that varied among the tested cancer cell lines; however, radiosensitization was undetectable in normal cells. Other commonly used PARPis, olaparib, veliparib, or rucaparib were ineffective radiosensitizers under our experimental conditions. Although genetic ablation or pharmacological inhibition of Polθ only mildly radiosensitized cancer cells, talazoparib-treated cells were markedly further radiosensitized. Mechanistically, talazoparib shunted DSBs to Polθ-dependent alt-EJ by enhancing DNA end-resection in a CtIP- and MRE11-dependent manner - an effect detectable at low, but not high IR doses. Chromosomal translocation analysis in talazoparib-treated cells exposed to Polθ inhibitors suggested that PARP1- and Polθ-dependent alt-EJ pathways may complement, but also back up each other.
Conclusion: We propose that talazoparib promotes low-dose, CtIP/MRE11-dependent resection and increases the reliance of irradiated HR-proficient cancer cells, on Polθ-mediated alt-EJ. The combination of Polθ inhibitors with talazoparib suppresses this option and causes further radiosensitization. The results suggest that Polθ inhibition may be exploited to maximize talazoparib radiosensitization of HR-proficient tumors in the clinic.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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