Radiotherapy-poly(ADP-ribose) polymerase inhibitor combinations: progress to date

Derby, S. J. , Chalmers, A. J. and Carruthers, R. (2022) Radiotherapy-poly(ADP-ribose) polymerase inhibitor combinations: progress to date. Seminars in Radiation Oncology, 32(1), pp. 15-28. (doi: 10.1016/j.semradonc.2021.09.005) (PMID:34861992)

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Radiation resistance remains a huge clinical problem for cancer patients and oncologists in the 21st century. In recent years, the mammalian DNA damage response (DDR) has been extensively characterized and shown to play a key role in determining cellular survival following ionizing radiation exposure. Genomic instability due to altered DDR is a hallmark of cancer, with many tumors exhibiting abnormal DNA repair or lack of redundancy in DDR. Targeting the abnormal DDR phenotype of tumor cells could lead to substantial gains in radiotherapy efficacy, improving local control and survival for patients with cancers that are refractory to current therapies. Poly(ADP-ribose) polymerase inhibitors (PARPi) are the most clinically advanced DDR inhibitors under investigation as radiosensitisers. Preclinical evidence suggests that PARPi may provide tumor specific radiosensitisation in certain contexts. In addition to inhibition of DNA single strand break repair, PARPi may offer other benefits in combination treatment including radiosensitisation of hypoxic cells and targeting of alternative repair pathways such as microhomology mediated end joining which are increasingly recognized to be upregulated in cancer. Several early phase clinical trials of PARPi with radiation have completed or are in progress. Early reports have highlighted tumor specific challenges, with tolerability dependent upon anatomical location and use of concomitant systemic therapies; these challenges were largely predicted by preclinical data. This review discusses the role of PARP in the cellular response to ionizing radiation, summarizes preclinical studies of PARPi in combination with radiotherapy and explores current early phase clinical trials that are evaluating these combinations.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Carruthers, Dr Ross and Chalmers, Professor Anthony and Derby, Dr Sarah
Authors: Derby, S. J., Chalmers, A. J., and Carruthers, R.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Seminars in Radiation Oncology
ISSN (Online):1532-9461
Published Online:30 November 2021
Copyright Holders:Copyright © 2021 Elsevier Inc.
First Published:First published in Seminars in Radiation Oncology 32(1): 15-28
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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