Targeting deficient DNA damage repair in gastric cancer

ABSTRACT

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.

KEYWORDS:

• Gastric adenocarcinoma
• DNA damage repair
• homologous recombination deficiency (HRD)
• BRCAness
• synthetic lethality
• PARP inhibitor
• ataxia telangiectasia mutated (ATM)

Article highlights

• Developments in recent years have greatly expanded our understanding of DNA damage repair pathways and of defects affecting these pathways.

• Deficiencies in Homologous Recombination (HR) are seen across multiple tumour types, including gastric cancer, and various signatures have been proposed as a means to detect these deficiencies including multi-gene signatures, structural rearrangement signatures and transcriptional signatures.

• In gastric cancer dysfunction or loss of ATM protein appears to be an important cause of HRD and may be associated with microsatellite instability (MSI)

• The phase II Study 39 reported an improvement in overall survival in the second line treatment of advanced gastric cancer with paclitaxel in combination with the PARP inhibitor olaparib, particularly in patients with low ATM protein levels

• Future studies investigating therapies targeting DNA damage repair in the maintenance setting, in Western patients and in combination with immunotherapy, chemotherapy, other targeted agents and radiotherapy will establish whether this approach has the potential to significantly improve outcomes in gastric cancer

• The development of predictive signatures or biomarkers and means to overcome treatment resistance will prove vital to the success or otherwise of this approach

This box summarizes key points contained in the article.

Declaration of interest

K Young is supported by the RMH ICR NIHR BRC. N Starling receives research funding from AstraZeneca, Pfizer and AbbVie. D Cunningham receives research funding from Amgen, AstraZeneca, Bayer, Celgene, Merck-Serono, Medimmune, Merrimack, Roche and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper is not funded.