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)

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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, Dr Nigel and Wright, Mr Derek and Dreyer, Dr Stephan and Serrels, Dr Bryan and Bailey, Dr Peter and Tesson, Dr Mathias and Rebus, Ms Selma and Lampraki, Dr Eirini-Maria and Evers, Ms Lisa and Bailey, Dr Ulla-Maja and Oien, Professor Karin and Upstill-Goddard, Dr Rosie and Biankin, Professor Andrew and McGregor, Dr Grant and Moran-Jones, Dr Kim and Duthie, Dr Fraser and Caligiuri, Giuseppina and Frame, Prof Margaret and Cunningham, Richard and Morton, Professor Jen and McKay, Mr Colin and Paulus-Hock, Mrs Viola and Chang, Professor David and Nourse, Dr Craig and Jones, Mr Marc 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 > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
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

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
169396Genotype Guided Stratified Therapy for Pancreatic CancerAndrew BiankinCancer Research UK (CRUK)C29717/A17263Institute of Cancer Sciences
169638Genotype Guided Stratified Therapy for Pancreatic CancerAndrew BiankinCancer Research UK (CRUK)C29717/A18484CS -Translational Research Centre
172008Clinical Training Award Cycle 2Andrew BiankinCancer Research UK (CRUK)C596/A20921CS -Translational Research Centre
174160Precision PancAndrew BiankinCancer Research UK (CRUK)C29717/A23526CS -Translational Research Centre
170634Defining Platinum and PARP Responsive Molecular Phenotypes of Pancreatic Cancer.Andrew BiankinWellcome Trust (WELLCOTR)103721/Z/14/ZInstitute of Cancer Sciences