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Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Stephan B Dreyer1, Rosie Upstill-Goddard2, Viola Paulus-Hock3

  • 1Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom.

Gastroenterology
|October 11, 2020
PubMed
Abstract

Insights

Pancreatic cancer (PC) therapies are challenging. This study identifies biomarkers for DNA damage response (DDR) deficiency and replication stress, guiding new targeted treatments for PC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Pancreatic cancer (PC) remains a highly lethal malignancy with limited therapeutic options.
  • Developing novel, biomarker-driven strategies is crucial for improving PC treatment outcomes.

Purpose of the Study:

  • To investigate the association between DNA damage response (DDR), replication stress, and therapeutic response in PC.
  • To establish a biomarker-driven strategy targeting DDR and replication stress for PC treatment.

Main Methods:

  • Interrogation of transcriptome, genome, proteome, and functional characteristics of 61 PC patient-derived cell lines.
  • Validation in patient-derived xenografts and human PC organoids.
  • Development of novel signatures for DDR deficiency and replication stress.

Main Results:

  • Biomarkers for DDR deficiency, including homologous recombination deficiency, correlate with response to platinum and PARP inhibitor therapies.
  • A novel replication stress signature predicts response to ATR and WEE1 inhibitor treatments.
  • Replication stress is prevalent in the squamous subtype of PC and independent of DDR deficiency.

Conclusions:

  • DDR deficiency and replication stress are distinct pathways in PC, offering therapeutic opportunities.
  • Targeting DDR and replication stress provides a promising avenue for novel PC therapies, even in DDR-proficient tumors or post-platinum treatment.
Keywords:
DNA Damage ResponsePancreatic CancerPersonalized MedicineReplication Stress

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