Journal
GASTROENTEROLOGY
Volume 160, Issue 1, Pages 362-+Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2020.09.043
Keywords
Pancreatic Cancer; DNA Damage Response; Replication Stress; Personalized Medicine
Categories
Funding
- National Health and Medical Research Council of Australia [631701, 535903, 427601]
- Queensland Government National and International Research Alliances Program (NIRAP)
- University of Queensland
- Institute for Molecular Bioscience
- Australian Government: Department of Innovation, Industry, Science and Research
- Australian Cancer Research Foundation
- Cancer Council New South Wales (NSW) [SRP06-01, SRP11-01.ICGC]
- Cancer Institute NSW [10/ECF/2-26, 06/ECF/1-24, 09/CDF/2-40, 07/CDF/1-03, 10/CRF/1-01, 08/RSA/1-15, 07/CDF/1-28, 10/CDF/2-26, 10/FRL/2-03, 06/RSA/1-05, 09/RIG/1-02, 10/TPG/1-04, 11/REG/1-10, 11/CDF/3-26]
- Garvan Institute of Medical Research
- Avner Nahmani Pancreatic Cancer Research Foundation
- R. T. Hall Trust
- Petre Foundation
- Philip Hemstritch Foundation
- Gastroenterological Society of Australia
- American Association for Cancer Research
- Landon Foundation-INNOVATOR Award
- Royal Australasian College of Surgeons
- Royal Australasian College of Physicians
- Royal College of Pathologists of Australasia
- Susan Wojcicki and Dennis Tropper
- National Institutes of Health grants [CA62924, 5R01CA150190-07, P50 CA102701]
- Cancer Research UK [C29717/A17263, C29717/A18484, C596/A18076, C596/A20921, A23526]
- Wellcome Trust [103721/Z/14/Z]
- Pancreatic Cancer UK Future Research Leaders Fund [FLF2015_04_Glasgow]
- Scottish Genome Partnership [SEHHD-CSO 1175759/2158447]
- MRC/EPSRC Glasgow Molecular Pathology Node
- Howat Foundation
- Italian Cancer Genome Project-Ministry of University [FIRB RBAP10AHJB]
- Associazione Italiana Ricerca Cancro [12182]
- FP7 European Community Grant Cam-Pac [602783]
- Italian Ministry of Health [FIMP-CUP_J33G13000210001]
- International Cancer Genome Consortium, Ontario Institute for Cancer Research
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DDR deficiency and replication stress are independent of each other, offering opportunities for therapy in DDR-proficient PC and after platinum therapy. Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors, including previously described molecular subtypes, and serve as a valuable model for studying novel therapeutic strategies targeting DDR and replication stress in PC.
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.
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