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Targeting deficient DNA damage repair in gastric cancer
Kate Young1, Naureen Starling1, David Cunningham1
1a Department of Medicine , The Royal Marsden NHS Foundation Trust, GI and Lymphoma Unit , Sutton , UK.
Introduction:
Over recent years our understanding of DNA damage repair has evolved leading to an expansion of therapies attempting to exploit DNA damage repair deficiencies across multiple solid tumours. Gastric cancer has been identified as a tumour where a subgroup of patients demonstrates deficiencies in the homologous recombination pathway providing a potential novel treatment approach for this poor prognosis disease.
Area Covered:
This review provides an overview of DNA damage repair and how this has been targeted to date in other tumour types exploiting the concept of synthetic lethality. This is followed by a discussion of how deficiencies in homologous recombination may be identified across tumour types and on recent progress in targeting DNA repair deficiencies in gastric cancer.
Expert Opinion:
Gastric cancer remains a difficult malignancy to treat and the possibility of targeting deficient DNA repair in a subgroup of patients is an exciting prospect. Future combinations with immunotherapy and radiotherapy are appealing and appear to have a sound biological rationale. However, much work remains to be done to understand the significance of the genetic and epigenetic alterations involved, to elucidate the optimum predictive signatures or biomarkers and to consider means of overcoming treatment resistance.
Insights
Targeting DNA damage repair deficiencies, particularly homologous recombination, offers a novel treatment strategy for gastric cancer. Further research is needed to identify biomarkers and overcome resistance for this poor prognosis disease.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Advances in understanding DNA damage repair (DDR) have spurred the development of targeted therapies for solid tumors.
- Gastric cancer, a disease with poor prognosis, presents an opportunity for novel treatment by targeting homologous recombination deficiencies in a patient subgroup.
Purpose of the Study:
- To review the concept of synthetic lethality in targeting DNA damage repair.
- To discuss the identification of homologous recombination deficiencies across tumor types.
- To highlight recent advancements in targeting DNA repair deficiencies specifically in gastric cancer.
Main Methods:
- Review of existing literature on DNA damage repair pathways and synthetic lethality.
- Analysis of methods for identifying homologous recombination deficiencies.
- Synthesis of current progress in gastric cancer therapeutic strategies targeting DNA repair.
Main Results:
- DNA damage repair deficiencies, including homologous recombination, can be exploited for therapeutic benefit.
- Biomarkers for identifying these deficiencies are crucial for patient stratification.
- Targeting DNA repair offers a promising avenue for treating gastric cancer.
Conclusions:
- Exploiting DNA repair deficiencies in gastric cancer is a promising therapeutic strategy.
- Future combinations with immunotherapy and radiotherapy show biological rationale.
- Further research is essential to understand genetic alterations, identify predictive biomarkers, and overcome treatment resistance.
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