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Page 4 van Waardenburg et al. Cancer Drug Resist 2021;4:837-41 https://dx.doi.org/10.20517/cdr.2021.80

presented, including inhibitors of DNA repair proteins, such as PARP, ATR, and DNA-PK, as well as cell
cycle checkpoints CHK1 and WEE1. The role of particle therapy (protons, carbon ions) in overcoming
radiation resistance is also discussed. As radiation is one of the main modalities of treatment for head and
neck cancer, there is a clear need to identify effective combinatorial strategies that can be tested in future
clinical trials.

In summary, more work is needed to advance the field regarding rationally combining therapies targeting
DNA repair with other agents, including immunotherapy. The best stimulus to further enhance the
targeting of DNA repair is the realization that cancer cells have a greater dependency on DNA damage
response and DNA repair than normal cells. Recent evidence also points to an interaction between DNA
damage and the immune system [18-20] , and multiple trials are ongoing that are investigating combinations of
DNA damage response targeting agents with immune checkpoint inhibitors. While these factors illustrate
the promise of targeting DNA damage response, a clinical challenge has been to ascertain for each patient
whether the cancer will have a long-term response to these agents. There is a dire need to uncover
additional biomarkers that predict response/resistance, including detection tools to identify a DNA repair
“fingerprint” as well as other oncogenic driver pathways in order to select the optimal therapeutic
combinations and to identify early relapse of the disease that may inform novel interventions to combat
resistance.

DECLARATIONS
Authors’ contributions
Wrote and reviewed the manuscript: van Waardenburg RCAM, Yang ES

Availability of data and materials
Not applicable.

Financial support and sponsorship
van Waardenburg RCAM in part funded by American Cancer Society UAB ACS-IRG Junior Faculty
Development Grant (ACS-IRG-60-001-53), Department of Defense OCRP pilot award W81XWH-15-1-
0198, and the National Institutes of Health Cancer Center Core Support Grant (P30CA013148) and
National Institutes of Health - National Institute of Disorders and Stroke (1R21NS116312-01A1).

Conflicts of interest
Both authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Copyright
© The Author(s) 2021.

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