Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Stephan B. Dreyer, Rosie Upstill-Goddard, Viola Paulus-Hock, Clara Paris, Eirini Maria Lampraki, Eloise Dray, Bryan Serrels, Giuseppina Caligiuri, Selma Rebus, Dennis Plenker, Zachary Galluzzo, Holly Brunton, Richard Cunningham, Mathias Tesson, Craig Nourse, Ulla Maja Bailey, Marc D. Jones, Kim Moran-Jones, Derek W. Wright, Fraser DuthieKarin Oien, Lisa Evers, Colin J. McKay, Grant A. McGregor, Aditi Gulati, Ilirjana Bajrami, Stephan Pettitt, Michele L. Dziubinski, Juliana Candido, Frances Balkwill, Simon T. Barry, Robert Grützmann, Lola Rahib, Glasgow Precision Oncology Laboratory,, Australian Pancreatic Cancer Genome Initiative, Amber L Johns, Marina Pajic, Fieke E.M. Froeling, Phillip Beer, Elizabeth A Musgrove, Gloria M. Petersen, Alan Ashworth, Margaret C. Frame, Howard C. Crawford, Diane M. Simeone, Chris Lord, Debabrata Mukhopadhyay, Christian Pilarsky, David A. Tuveson, Susanna L. Cooke, Nigel Balfour Jamieson, Jennifer P. Morton, Owen J. Sansom, Peter J. Bailey, Andrew V Biankin, David K. Chang

Research output: Contribution to journalArticleResearchpeer-review

71 Citations (Scopus)

Abstract

Background & Aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress, and novel therapeutic response in PC to develop a biomarker-driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome, and functional characteristics of 61 novel PC patient–derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient-derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors, including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, cosegregates with response to platinum (P <.001) and PARP inhibitor therapy (P <.001) in vitro and in vivo. We generated a novel signature of replication stress that predicts response to ATR (P <.018) and WEE1 inhibitor (P <.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P <.001) but was not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy.

Original languageEnglish
Pages (from-to)362-377.e13
Number of pages29
JournalGastroenterology
Volume160
Issue number1
DOIs
Publication statusPublished - Jan 2021
Externally publishedYes

Keywords

  • DNA Damage Response
  • Pancreatic Cancer
  • Personalized Medicine
  • Replication Stress

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