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Review
. 2022 Nov 24;23(23):14672.
doi: 10.3390/ijms232314672.

DNA Damage Response in Cancer Therapy and Resistance: Challenges and Opportunities

Dana Jurkovicova  1 , Christiana M Neophytou  2 , Ana Čipak Gašparović  3 , Ana Cristina Gonçalves  4   5   6
Affiliations
Review

DNA Damage Response in Cancer Therapy and Resistance: Challenges and Opportunities

Dana Jurkovicova et al. Int J Mol Sci. .

Abstract

Resistance to chemo- and radiotherapy is a common event among cancer patients and a reason why new cancer therapies and therapeutic strategies need to be in continuous investigation and development. DNA damage response (DDR) comprises several pathways that eliminate DNA damage to maintain genomic stability and integrity, but different types of cancers are associated with DDR machinery defects. Many improvements have been made in recent years, providing several drugs and therapeutic strategies for cancer patients, including those targeting the DDR pathways. Currently, poly (ADP-ribose) polymerase inhibitors (PARP inhibitors) are the DDR inhibitors (DDRi) approved for several cancers, including breast, ovarian, pancreatic, and prostate cancer. However, PARPi resistance is a growing issue in clinical settings that increases disease relapse and aggravate patients' prognosis. Additionally, resistance to other DDRi is also being found and investigated. The resistance mechanisms to DDRi include reversion mutations, epigenetic modification, stabilization of the replication fork, and increased drug efflux. This review highlights the DDR pathways in cancer therapy, its role in the resistance to conventional treatments, and its exploitation for anticancer treatment. Biomarkers of treatment response, combination strategies with other anticancer agents, resistance mechanisms, and liabilities of treatment with DDR inhibitors are also discussed.

Keywords: DNA damage repair inhibitors; DNA damage response; biomarkers; drug resistance.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mechanisms of resistance to DDR inhibitors. Cancer cells develop resistance to DDR through several mechanisms. The molecular mechanisms of resistance to PARPi include HR capacity restoration, decreased trapping of PARP1, stabilization of replication forks, and P-gp-mediated drug efflux. The resistance to WEE1 inhibitor is induced by AXL overexpression, mTOR signaling, CHK1 activation, and through the overexpression of MYT1 that decrease CDK1 activity. The resistance to CHK1 inhibitor is associated with increased E2F/G2M/SAC expression and reduced replication stress. The resistance to ATR inhibitor is induced by the loss of PGBD5 and CDC25A deficiency. Finally, the DNA-PK inhibitor resistance is caused by the loss of MLH1/MSH3 and the overexpression of ABCG2.
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