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Harnessing DNA Double-Strand Break Repair for Cancer Treatment
Anika Trenner1, Alessandro A Sartori1
1Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
Abstract:
DNA double-strand breaks (DSBs) are highly deleterious, with a single unrepaired DSB being sufficient to trigger cell death. Compared to healthy cells, cancer cells have a higher DSB burden due to oncogene-induced replication stress and acquired defects in DNA damage response (DDR) mechanisms. Consequently, hyperproliferating cancer cells rely on efficient DSB repair for their survival. Moreover, augmented DSB repair capacity is a major cause of radio- and chemoresistance and, ultimately, cancer recurrence. Although inherited DDR defects can predispose individuals to develop certain cancers, the very same vulnerability may be therapeutically exploited to preferentially kill tumor cells. A paradigm for DNA repair targeted therapy has emerged in cancers that exhibit mutations in BRCA1 or BRCA2 tumor suppressor genes, conferring a strong defect in homologous recombination, a major and error-free DSB repair pathway. Clinical validation of such approaches, commonly described as synthetic lethality (SL), has been provided by the regulatory approval of poly(ADP-ribose) polymerase 1 inhibitors (PARPi) as monotherapy for BRCA1/2-mutated breast and ovarian tumors. In this review, we will describe the different DSB repair mechanisms and discuss how their specific features could be exploited for cancer therapy. A major emphasis is put on advances in combinatorial treatment modalities and SL approaches arising from DSB repair pathway interdependencies.
Insights
Cancer cells have a high DNA double-strand break (DSB) burden and rely on DNA damage response (DDR) for survival. Exploiting DDR defects, like in BRCA1/2 mutations, offers targeted cancer therapy strategies.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Cancer cells exhibit elevated DNA double-strand breaks (DSBs) due to oncogenic stress and impaired DNA damage response (DDR) mechanisms.
- Efficient DSB repair is crucial for cancer cell survival, contributing to radio- and chemoresistance and tumor recurrence.
- Inherited DDR defects can increase cancer susceptibility but also represent a therapeutic vulnerability.
Purpose of the Study:
- To review diverse DNA double-strand break repair mechanisms.
- To discuss therapeutic strategies exploiting DSB repair pathways for cancer treatment.
- To highlight advances in combinatorial therapies and synthetic lethality (SL) approaches.
Main Methods:
- Review of scientific literature on DNA double-strand break repair pathways.
- Analysis of therapeutic strategies targeting DNA repair mechanisms in cancer.
- Discussion of synthetic lethality principles and clinical applications.
Main Results:
- Cancer cells' reliance on DSB repair creates a vulnerability exploitable for targeted therapies.
- Mutations in BRCA1/2 genes impair homologous recombination, a key error-free DSB repair pathway.
- Poly(ADP-ribose) polymerase 1 inhibitors (PARPi) demonstrate clinical efficacy in BRCA1/2-mutated cancers.
Conclusions:
- Targeting DSB repair pathways, particularly through synthetic lethality, offers a promising avenue for cancer therapy.
- Understanding DSB repair interdependencies can lead to novel combinatorial treatment strategies.
- Exploiting cancer-specific DDR defects holds potential for improving treatment outcomes and overcoming resistance.
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02:04Fixing Double-strand Breaks
02:04Fixing Double-strand Breaks
02:31Homologous Recombination
02:36DNA Damage can Stall the Cell Cycle
02:36DNA Damage Can Stall the Cell Cycle
02:25Overview of DNA Repair
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