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Assessment of Global DNA Double-Strand End Resection using BrdU-DNA Labeling coupled with Cell Cycle Discrimination Imaging
Published on: April 28, 2021
Targeting DNA repair pathway in cancer: Mechanisms and clinical application
Manni Wang1, Siyuan Chen1, Danyi Ao1
1Department of Biotherapy Cancer Center West China Hospital Sichuan University Chengdu China.
Abstract:
Over the last decades, the growing understanding on DNA damage response (DDR) pathways has broadened the therapeutic landscape in oncology. It is becoming increasingly clear that the genomic instability of cells resulted from deficient DNA damage response contributes to the occurrence of cancer. One the other hand, these defects could also be exploited as a therapeutic opportunity, which is preferentially more deleterious in tumor cells than in normal cells. An expanding repertoire of DDR-targeting agents has rapidly expanded to inhibitors of multiple members involved in DDR pathways, including PARP, ATM, ATR, CHK1, WEE1, and DNA-PK. In this review, we sought to summarize the complex network of DNA repair machinery in cancer cells and discuss the underlying mechanism for the application of DDR inhibitors in cancer. With the past preclinical evidence and ongoing clinical trials, we also provide an overview of the history and current landscape of DDR inhibitors in cancer treatment, with special focus on the combination of DDR-targeted therapies with other cancer treatment strategies.
Insights
Targeting DNA damage response (DDR) pathways offers new cancer therapies. Exploiting cancer cell DNA repair defects with DDR inhibitors, like PARP inhibitors, shows promise, especially in combination treatments.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Understanding of DNA damage response (DDR) pathways has significantly advanced cancer therapeutics.
- Genomic instability from deficient DDR is a hallmark of cancer.
- Tumor-specific DDR defects present therapeutic vulnerabilities.
Purpose of the Study:
- To review the complex DNA repair network in cancer cells.
- To discuss the mechanisms of DDR inhibitors in cancer treatment.
- To provide an overview of current DDR inhibitors and combination strategies.
Main Methods:
- Literature review of preclinical evidence and clinical trials.
- Analysis of the mechanisms of action for various DDR inhibitors.
- Synthesis of information on combination therapies.
Main Results:
- An expanding array of DDR inhibitors targeting key pathway members (e.g., PARP, ATM, ATR) are available.
- DDR inhibitors demonstrate therapeutic potential by exploiting cancer-specific defects.
- Combination strategies involving DDR inhibitors are under active investigation.
Conclusions:
- DDR inhibitors represent a significant advancement in oncology.
- Exploiting DDR pathways offers a promising avenue for cancer treatment.
- Further research into combination therapies is crucial for maximizing clinical benefit.
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