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Fabbrizi et al. Cancer Drug Resist 2020;3:775-90 Cancer
DOI: 10.20517/cdr.2020.49 Drug Resistance

Review Open Access

Radiotherapy and the cellular DNA damage
response: current and future perspectives on head

and neck cancer treatment

Maria Rita Fabbrizi , Jason L. Parsons 1,2
1
1 Cancer Research Centre, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L3 9TA,
United Kingdom.
2 Clatterbridge Cancer Centre NHS Foundation Trust, Clatterbridge Road, Bebington CH63 4JY, United Kingdom.

Correspondence to: Dr. Jason L. Parsons, Cancer Research Centre, Department of Molecular and Clinical Cancer Medicine,
University of Liverpool, 200 London Road, Liverpool L3 9TA, United Kingdom. E-mail: j.parsons@liverpool.ac.uk

How to cite this article: Fabbrizi MR, Parsons JL. Radiotherapy and the cellular DNA damage response: current and future
perspectives on head and neck cancer treatment. Cancer Drug Resist 2020;3:775-90.
http://dx.doi.org/10.20517/cdr.2020.49
Received: 2 Jul 2020 First Decision: 31 Aug 2020 Revised: 1 Sep 2020 Accepted: 4 Sep 2020 Available online: 17 Sep 2020

Academic Editor: Robert C. A. M. van Waardenburg Copy Editor: Cai-Hong Wang Production Editor: Jing Yu

Abstract
Incidences of head and neck squamous cell carcinoma (HNSCC) have been on the rise in the last few decades,
with a significant risk factor being human papillomavirus (HPV) type-16/18 infection, particularly in the
development of oropharyngeal cancers. Radiotherapy (RT) is an important treatment modality for HNSCC, where
it promotes extensive cellular DNA damage leading to the therapeutic effect. It has been well-established that
HPV-positive HNSCC display better response rates and improved survival following RT compared to HPV-negative
HNSCC. The differential radiosensitivity has been largely associated with altered cellular DNA damage response
mechanisms in HPV-positive HNSCC, and particularly with the signaling and repair of DNA double strand breaks.
However, other factors, particularly hypoxia present within the solid cancer, have a major impact on relative
radioresistance. Consequently, recent approaches aimed at enhancing the radiosensitivity of HNSCC have largely
centered on targeting key proteins involved in DNA repair, DNA damage checkpoint activation, and hypoxia
signaling. These studies have utilised in vitro and in vivo models of HPV-positive and HPV-negative HNSCC and
examined the impact of specific inhibitors against the targets in combination with radiation in suppressing HNSCC
cell growth and survival. Here, accumulating evidence has shown that targeting enzymes including poly (ADP-
ribose) polymerase, ataxia telangiectasia and Rad-3 related, DNA-dependent protein kinase catalytic subunit, and
checkpoint kinase 1 can radiosensitise HNSCC cells which should be taken forward in further preclinical studies,
with the goal of optimizing the future effective RT treatment of HNSCC.

© The Author(s) 2020. 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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