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Targeting DNA Double-Strand Break Repair Pathways to Improve Radiotherapy Response

Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Roentgenweg 11, 72076 Tuebingen, Germany
Genes 2019, 10(1), 25; https://doi.org/10.3390/genes10010025
Received: 9 November 2018 / Revised: 7 December 2018 / Accepted: 27 December 2018 / Published: 4 January 2019
(This article belongs to the Special Issue DNA Damage and Repair in Cancer)
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Abstract

More than half of cancer patients receive radiotherapy as a part of their cancer treatment. DNA double-strand breaks (DSBs) are considered as the most lethal form of DNA damage and a primary cause of cell death and are induced by ionizing radiation (IR) during radiotherapy. Many malignant cells carry multiple genetic and epigenetic aberrations that may interfere with essential DSB repair pathways. Additionally, exposure to IR induces the activation of a multicomponent signal transduction network known as DNA damage response (DDR). DDR initiates cell cycle checkpoints and induces DSB repair in the nucleus by non-homologous end joining (NHEJ) or homologous recombination (HR). The canonical DSB repair pathways function in both normal and tumor cells. Thus, normal-tissue toxicity may limit the targeting of the components of these two pathways as a therapeutic approach in combination with radiotherapy. The DSB repair pathways are also stimulated through cytoplasmic signaling pathways. These signaling cascades are often upregulated in tumor cells harboring mutations or the overexpression of certain cellular oncogenes, e.g., receptor tyrosine kinases, PIK3CA and RAS. Targeting such cytoplasmic signaling pathways seems to be a more specific approach to blocking DSB repair in tumor cells. In this review, a brief overview of cytoplasmic signaling pathways that have been reported to stimulate DSB repair is provided. The state of the art of targeting these pathways will be discussed. A greater understanding of the underlying signaling pathways involved in DSB repair may provide valuable insights that will help to design new strategies to improve treatment outcomes in combination with radiotherapy. View Full-Text
Keywords: double-strand break repair; ionizing radiation; signal transduction; molecular targeting; radiosensitization double-strand break repair; ionizing radiation; signal transduction; molecular targeting; radiosensitization
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Toulany, M. Targeting DNA Double-Strand Break Repair Pathways to Improve Radiotherapy Response. Genes 2019, 10, 25.

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