Targeting DNA damage response and replication stress in pancreatic cancer

Dreyer, S. B. et al. (2021) Targeting DNA damage response and replication stress in pancreatic cancer. Gastroenterology, 160(1), pp. 362-377. (doi: 10.1053/j.gastro.2020.09.043) (PMID:33039466) (PMCID:PMC8167930)

Abstract

Background and 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, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but 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 post-platinum therapy.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jamieson, Professor Nigel and Wright, Mr Derek and Dreyer, Dr Stephan and Serrels, Dr Bryan and Tesson, Dr Mathias and Rebus, Ms Selma and Lampraki, Dr Eirini-Maria and Biankin, Professor Andrew and Moran-Jones, Dr Kim and Cunningham, Richard and Jones, Mr Marc and Nourse, Dr Craig and Bailey, Dr Peter and Evers, Ms Lisa and Bailey, Dr Ulla-Maja and Oien, Professor Karin and Upstill-Goddard, Dr Rosie and McGregor, Dr Grant and Duthie, Dr Fraser and Caligiuri, Giuseppina and Frame, Prof Margaret and Morton, Professor Jen and McKay, Mr Colin and Paulus-Hock, Mrs Viola and Chang, Professor David and Sansom, Professor Owen
• Authors: Dreyer, S. B., Upstill-Goddard, R., Paulus-Hock, V., Paris, C., Lampraki, E.-M., Dray, E., Serrels, B., Caligiuri, G., Rebus, S., Plenker, D., Galluzzo, Z., Brunton, H., Cunningham, R., Tesson, M., Nourse, C., Bailey, U.-M., Jones, M., Moran-Jones, K., Wright, D. W., Duthie, F., Oien, K., Evers, L., McKay, C. J., McGregor, G. A., Gulati, A., Brough, R., Bajrami, I., Pettitt, S., Dziubinski, M. L., Candido, J., Balkwill, F., Barry, S. T., Grützmann, R., Rahib, L., Glasgow Precision Oncology Laboratory, , Australian Pancreatic Cancer Genome Initiative, , Johns, A., Pajic, M., Froeling, F. E.M., Beer, P., Musgrove, E. A., Petersen, G. M., Ashworth, A., Frame, M. C., Crawford, H. C., Simeone, D. M., Lord, C., Mukhopadhyay, D., Pilarsky, C., Tuveson, D. A., Cooke, S. L., Jamieson, N. B., Morton, J. P., Sansom, O. J., Bailey, P. J., Biankin, A. V., and Chang, D. K.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Gastroenterology
• Publisher: Elsevier
• ISSN: 0016-5085
• ISSN (Online): 1528-0012
• Published Online: 09 October 2020
• Copyright Holders: Copyright © 2021 by AGA Institute
• First Published: First published in Gastroenterology 160(1):362-377
• Publisher Policy: Reproduced under a Creative Commons licence

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
169396		Genotype Guided Stratified Therapy for Pancreatic Cancer	Andrew Biankin	Cancer Research UK (CRUK)	C29717/A17263	Institute of Cancer Sciences
169638		Genotype Guided Stratified Therapy for Pancreatic Cancer	Andrew Biankin	Cancer Research UK (CRUK)	C29717/A18484	CS -Translational Research Centre
172008		Clinical Training Award Cycle 2	Andrew Biankin	Cancer Research UK (CRUK)	C596/A20921	CS -Translational Research Centre
174160		Precision Panc	Andrew Biankin	Cancer Research UK (CRUK)	C29717/A23526	CS -Translational Research Centre
170634		Defining Platinum and PARP Responsive Molecular Phenotypes of Pancreatic Cancer.	Andrew Biankin	Wellcome Trust (WELLCOTR)	103721/Z/14/Z	Institute of Cancer Sciences