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DNA Damage-Inducing Anticancer Therapies: From Global to Precision Damage
Thom G A Reuvers1,2, Roland Kanaar1,3, Julie Nonnekens1,2,3
1Department of Molecular Genetics, Erasmus MC, Dr. Molenwaterplein 40, 3015 GD Rotterdam, The Netherlands.
Abstract:
DNA damage-inducing therapies are of tremendous value for cancer treatment and function by the direct or indirect formation of DNA lesions and subsequent inhibition of cellular proliferation. Of central importance in the cellular response to therapy-induced DNA damage is the DNA damage response (DDR), a protein network guiding both DNA damage repair and the induction of cancer-eradicating mechanisms such as apoptosis. A detailed understanding of DNA damage induction and the DDR has greatly improved our knowledge of the classical DNA damage-inducing therapies, radiotherapy and cytotoxic chemotherapy, and has paved the way for rational improvement of these treatments. Moreover, compounds targeting specific DDR proteins, selectively impairing DNA damage repair in cancer cells, form a promising novel therapy class that is now entering the clinic. In this review, we give an overview of the current state and ongoing developments, and discuss potential avenues for improvement for DNA damage-inducing therapies, with a central focus on the role of the DDR in therapy response, toxicity and resistance. Furthermore, we describe the relevance of using combination regimens containing DNA damage-inducing therapies and how they can be utilized to potentiate other anticancer strategies such as immunotherapy.
Insights
DNA damage therapies are crucial for cancer treatment, working by damaging DNA and inhibiting cell growth. The DNA damage response (DDR) network is key to repair and cancer cell death, guiding therapy improvements and new drug development.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- DNA damage-inducing therapies, including radiotherapy and chemotherapy, are vital cancer treatments.
- The DNA damage response (DDR) network plays a critical role in managing DNA lesions, influencing repair, apoptosis, and cellular proliferation.
Purpose of the Study:
- To review the current understanding of DNA damage induction and the DDR in cancer therapy.
- To explore advancements in DNA damage-inducing therapies and targeted DDR inhibitors.
- To discuss the role of DDR in therapy response, toxicity, resistance, and combination strategies.
Main Methods:
- Literature review of DNA damage-inducing therapies and the DNA damage response.
- Analysis of current clinical developments and future directions for DDR-targeted agents.
- Examination of combination regimens involving DNA damage therapies and immunotherapy.
Main Results:
- Detailed understanding of DNA damage and DDR has improved conventional therapies.
- Targeting DDR proteins represents a promising new therapeutic strategy entering clinical practice.
- Combination therapies, including immunotherapy, can potentiate anticancer effects.
Conclusions:
- The DDR is central to the efficacy, toxicity, and resistance of DNA damage-inducing cancer therapies.
- Targeted DDR inhibition offers a novel therapeutic avenue.
- Strategic combinations of DNA damage therapies with other treatments, like immunotherapy, hold significant potential for enhanced cancer eradication.
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