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DNA Damage Response in Cancer Therapy and Resistance: Challenges and Opportunities
Dana Jurkovicova1, Christiana M Neophytou2, Ana Čipak Gašparović3
1Department of Genetics, Cancer Research Institute, Biomedical Research Center, v.v.i. of the Slovak Academy of Sciences, 845 05 Bratislava, Slovakia.
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.
Insights
Cancer patients often develop resistance to treatments, necessitating new therapies. DNA damage response inhibitors (DDRi), like PARP inhibitors, are promising but face resistance issues due to mechanisms like mutations and epigenetic changes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Chemo- and radiotherapy resistance is a significant challenge in cancer treatment.
- Defects in DNA damage response (DDR) pathways are common in various cancers.
- Targeting DDR pathways offers a promising therapeutic strategy for cancer patients.
Purpose of the Study:
- To review the role of DDR pathways in cancer therapy and treatment resistance.
- To discuss the mechanisms underlying resistance to DNA damage response inhibitors (DDRi).
- To explore strategies for overcoming DDRi resistance and improving patient outcomes.
Main Methods:
- Literature review of studies on DNA damage response pathways in cancer.
- Analysis of mechanisms of resistance to conventional treatments and DDR inhibitors.
- Discussion of therapeutic strategies involving DDR inhibitors, including combination therapies and biomarkers.
Main Results:
- Poly (ADP-ribose) polymerase inhibitors (PARP inhibitors) are approved DDR inhibitors for several cancers.
- Resistance to PARP inhibitors and other DDR inhibitors is an emerging clinical problem.
- Identified resistance mechanisms include reversion mutations, epigenetic modifications, replication fork stabilization, and increased drug efflux.
Conclusions:
- DNA damage response pathways are crucial targets for cancer therapy.
- Understanding and overcoming resistance mechanisms to DDR inhibitors is essential for improving treatment efficacy.
- Combination strategies and biomarker identification hold promise for enhancing DDR inhibitor-based cancer treatments.
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