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Nickoloff et al. Cancer Drug Resist 2021;4:244-63 Cancer
DOI: 10.20517/cdr.2020.89 Drug Resistance

Review Open Access

Exploiting DNA repair pathways for tumor
sensitization, mitigation of resistance, and normal

tissue protection in radiotherapy

Jac A. Nickoloff, Lynn Taylor, Neelam Sharma, Takamitsu A. Kato

Department of Environmental and Radiological Health Sciences, Colorado State University, Ft. Collins, CO 80523, USA.

Correspondence to: Dr. Jac A. Nickoloff, Department of Environmental and Radiological Health Sciences, Colorado State
University, 1681 Campus Delivery, Ft. Collins, CO 80523-1681, USA. E-mail: J.Nickoloff@colostate.edu
How to cite this article: Nickoloff JA, Taylor L, Sharma N, Kato TA. Exploiting DNA repair pathways for tumor sensitization,
mitigation of resistance, and normal tissue protection in radiotherapy. Cancer Drug Resist 2021;4:244-63.
http://dx.doi.org/10.20517/cdr.2020.89

Received: 29 Sep 2020 First Decision: 6 Nov 2020 Revised: 17 Nov 2020 Accepted: 3 Dec 2020 Available online: 19 Jun 2021
Academic Editors: Godefridus J. Peters, Robert C.A.M. van Waardenburg, Eddy S. Yang Copy Editor: Miao Zhang Production Editor: Jing Yu

Abstract
More than half of cancer patients are treated with radiotherapy, which kills tumor cells by directly and indirectly
inducing DNA damage, including cytotoxic DNA double-strand breaks (DSBs). Tumor cells respond to these
threats by activating a complex signaling network termed the DNA damage response (DDR). The DDR arrests
the cell cycle, upregulates DNA repair, and triggers apoptosis when damage is excessive. The DDR signaling and
DNA repair pathways are fertile terrain for therapeutic intervention. This review highlights strategies to improve
therapeutic gain by targeting DDR and DNA repair pathways to radiosensitize tumor cells, overcome intrinsic and
acquired tumor radioresistance, and protect normal tissue. Many biological and environmental factors determine
tumor and normal cell responses to ionizing radiation and genotoxic chemotherapeutics. These include cell type
and cell cycle phase distribution; tissue/tumor microenvironment and oxygen levels; DNA damage load and quality;
DNA repair capacity; and susceptibility to apoptosis or other active or passive cell death pathways. We provide an
overview of radiobiological parameters associated with X-ray, proton, and carbon ion radiotherapy; DNA repair and
DNA damage signaling pathways; and other factors that regulate tumor and normal cell responses to radiation. We
then focus on recent studies exploiting DSB repair pathways to enhance radiotherapy therapeutic gain.

Keywords: DNA repair, DNA double-strand break repair, non-homologous end-joining, homologous recombination,
radiosensitization, radioprotection, cancer therapy

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.

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