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Page 776 Fabbrizi et al. Cancer Drug Resist 2020;3:775-90 I http://dx.doi.org/10.20517/cdr.2020.49

Keywords: DNA damage, DNA repair, head and neck cancer, ionising radiation, proton beam therapy, radiobiology,
radiotherapy

INTRODUCTION
Head and neck cancer describes several different malignant tumors that develop in or around the throat,
larynx, nose, sinuses, and mouth. They usually develop in the squamous cells of the mucosal surfaces and
therefore are often referred to as head and neck squamous cell carcinoma (HNSCC). In the UK, HNSCC is
the 8th most common cancer with 12,200 new cases every year, the majority occurring in men (69%). Since
the early 1990s, HNSCC incidence rates have increased by ~30% in the UK. One year survival rates among
HNSCC subtypes are reportedly highest in salivary gland cancer (~60%) and lowest in hypopharyngeal
cancer (~20%) [1-4] . Tobacco and alcohol use are the common risk factors associated with HNSCC.
Furthermore, infection by high-risk (type-16/18) human papillomaviruses (HPVs) causes development
of HNSCC, particularly in cancers of the oropharynx (~40%-60% incidence). Importantly, patients with
HPV-positive HNSCC are known to have a better prognosis and improved survival rates associated with
an improved response to radiotherapy (RT) and chemotherapy as compared with HPV-negative HNSCC.
This reflects the different molecular mechanisms and biological characteristics underlying the oncogenic
[5]
processes .
Treatment of HNSCC invariably include surgery, RT, and chemotherapy, either as a single treatment or
in combination. The choice of one treatment over another is strongly influenced by the stage of disease
[6]
at diagnosis . While X-rays are used as a conventional RT treatment for HNSCC, major advancements
[7]
have been achieved with the introduction of proton beam therapy and the development of 3D conformal
[8]
stereotactic RT , which allow a better and safer treatment for the patients. The introduction of adaptive
RT as a special form of image-guided RT has also been significant . Nevertheless, all RT techniques target
[9]
and damage the DNA within the cancer cells leading to the therapeutic effect. Whilst RT promotes largely
the formation of DNA base damage and DNA single-strand breaks (SSBs), more important is the induction
of potentially toxic DNA lesions including DNA double strand breaks (DSBs) and complex DNA damage
(CDD), containing multiple DNA damage types including DNA base damage, abasic sites, and SSBs and
DSBs within close proximity (1-2 helical turns of the DNA). These DNA lesions trigger the activation of
the cellular DNA damage response (DDR), involving several cellular proteins and pathways that attempt to
[10]
repair and restore the integrity of the DNA . Depending on which cell cycle stage the cell is in, DSBs can
be resolved though the activation of two different repair pathways, namely non-homologous end-joining
(NHEJ) and homologous recombination (HR) [11-13] . The ultimate aim of RT is to create sufficient and/or
persistent DNA damage in the cancer cells that exceeds the cellular capacity for repair, which ultimately
triggers the cell death response or blocks their potential to replicate. This goal can be reached more
effectively by combining RT with chemotherapeutics, specifically those that inhibit the DNA repair or cell
cycle machinery.

In this review, we describe the effects of RT on DNA damage and the cellular DDR pathways responsible for
DNA repair. We also provide an up-to-date summary of the biological mechanisms critical in controlling
radiosensitivity of HNSCC, as well as current radiosensitisation strategies being explored for improving the
outcome of HNSCC patients post-RT.

THE CELLULAR DDR FOLLOWING RADIOTHERAPY
RT is a non-invasive treatment method that has certain advantages over chemotherapy or surgery,
especially when the cancer is not resectable, and it is the elective treatment for the majority of HNSCC.
In order to kill cancer cells, RT damages the DNA either directly or indirectly through ionisation of water