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 Jones; Kim Moran-Jones; Derek W. Wright; Fraser Duthie; Karin Oien; Lisa Evers; Colin J. McKay; Grant A. McGregor; Aditi Gulati; Rachel Brough; 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 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 B. Jamieson; Jennifer P. Morton; Owen J. Sansom; Peter J. Bailey; Andrew V. Biankin; David K. Chang

doi:10.1053/j.gastro.2020.09.043

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 Jones, Kim Moran-Jones, Derek W. Wright, Fraser DuthieKarin Oien, Lisa Evers, Colin J. McKay, Grant A. McGregor, Aditi Gulati, Rachel Brough, 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 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 B. Jamieson, Jennifer P. Morton, Owen J. Sansom, Peter J. Bailey, Andrew V. Biankin, David K. Chang^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

77 Citations (Scopus)

28 Downloads (Pure)

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 language	English
Pages (from-to)	362-377
Number of pages	29
Journal	Gastroenterology
Volume	160
Issue number	1
Early online date	8 Oct 2020
DOIs	https://doi.org/10.1053/j.gastro.2020.09.043
Publication status	Published - Jan 2021
Externally published	Yes

Bibliographical note

Copyright the AGA Institute 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

DNA Damage Response
Pancreatic Cancer
Personalized Medicine
Replication Stress

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10.1053/j.gastro.2020.09.043Licence: CC BY

Publisher version (open access)Final published version, 8.71 MBLicence: CC BY

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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., ... Chang, D. K. (2021). Targeting DNA damage response and replication stress in pancreatic cancer. Gastroenterology, 160(1), 362-377. https://doi.org/10.1053/j.gastro.2020.09.043

@article{8aded2fe59b8450299b8edda4101efa8,

title = "Targeting DNA damage response and replication stress in pancreatic cancer",

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.",

keywords = "DNA Damage Response, Pancreatic Cancer, Personalized Medicine, Replication Stress",

author = "Dreyer, {Stephan B.} and Rosie Upstill-Goddard and Viola Paulus-Hock and Clara Paris and Lampraki, {Eirini Maria} and Eloise Dray and Bryan Serrels and Giuseppina Caligiuri and Selma Rebus and Dennis Plenker and Zachary Galluzzo and Holly Brunton and Richard Cunningham and Mathias Tesson and Craig Nourse and Ulla-Maja Bailey and Marc Jones and Kim Moran-Jones and Wright, {Derek W.} and Fraser Duthie and Karin Oien and Lisa Evers and McKay, {Colin J.} and McGregor, {Grant A.} and Aditi Gulati and Rachel Brough and Ilirjana Bajrami and Stephan Pettitt and Dziubinski, {Michele L.} and Juliana Candido and Frances Balkwill and Barry, {Simon T.} and Robert Gr{\"u}tzmann and Lola Rahib and {Glasgow Precision Oncology Laboratory} and Sarah Allison and Dario Beraldi and Euan Cameron and Paul Grimwood and Shane Kelly and John Marshall and Sancha Martin and Brian McDade and Daniel McElroy and Donna Ramsay and Jane Hair and Paul Westwood and Nicola Williams and {Australian Pancreatic Cancer Genome Initiative} and Amanda Mawson and Scarlett, {Christopher J.} and Brancato, {Mary-Anne L.} and Rowe, {Sarah J.} and Simpson, {Skye H.} and Mona Martyn-Smith and Thomas, {Michelle T.} and Chantrill, {Lorraine A.} and Chin, {Venessa T.} and Angela Chou and Cowley, {Mark J.} and Humphris, {Jeremy L.} and Mead, {R. Scott} and Nagrial, {Adnan M.} and Jessica Pettit and Mark Pinese and Ilse Rooman and Jianmin Wu and Jiang Tao and Renee DiPietro and Clare Watson and Angela Steinmann and Lee, {Hong Ching} and Rachel Wong and Pinho, {Andreia V.} and Marc Giry-Laterriere and Daly, {Roger J.} and Sutherland, {Robert L.} and Grimmond, {Sean M.} and Nicola Waddell and Kassahn, {Karin S.} and Miller, {David K.} and Wilson, {Peter J.} and Patch, {Ann Marie} and Sarah Song and Ivon Harliwong and Senel Idrisoglu and Ehsan Nourbakhsh and Suzanne Manning and Shivangi Wani and Milena Gongora and Matthew Anderson and Oliver Holmes and Conrad Leonard and Darrin Taylor and Scott Wood and Christina Xu and Katia Nones and Fink, {J. Lynn} and Angelika Christ and Tim Bruxner and Nicole Cloonan and Felicity Newell and Pearson, {John V.} and Michael Quinn and Shivashankar Nagaraj and Stephen Kazakoff and Nick Waddell and Keerthana Krisnan and Kelly Quek and David Wood and Samra, {Jaswinder S.} and Gill, {Anthony J.} and Nick Pavlakis and Alex Guminski and Christopher Toon and Ray Asghari and Merrett, {Neil D.} and Darren Pavey and Amitabha Das and Cosman, {Peter H.} and Kasim Ismail and Chelsie O'Connnor and Lam, {Vincent W.} and Duncan McLeod and Pleass, {Henry C.} and Arthur Richardson and Virginia James and Kench, {James G.} and Cooper, {Caroline L.} and David Joseph and Charbel Sandroussi and Michael Crawford and James Gallagher and Michael Texler and Cindy Forest and Andrew Laycock and Epari, {Krishna P.} and Mo Ballal and Fletcher, {David R.} and Sanjay Mukhedkar and Spry, {Nigel A.} and Bastiaan DeBoer and Ming Chai and Nikolajs Zeps and Maria Beilin and Kynan Feeney and Nguyen, {Nan Q.} and Ruszkiewicz, {Andrew R.} and Chris Worthley and Tan, {Chuan P.} and Tamara Debrencini and John Chen and Brooke-Smith, {Mark E.} and Virginia Papangelis and Henry Tang and Barbour, {Andrew P.} and Clouston, {Andrew D.} and Patrick Martin and O'Rourke, {Thomas J.} and Amy Chiang and Fawcett, {Jonathan W.} and Kellee Slater and Shinn Yeung and Michael Hatzifotis and Peter Hodgkinson and Christopher Christophi and Mehrdad Nikfarjam and Angela Mountain and Biobank, {Victorian Cancer} and Eshleman, {James R.} and Hruban, {Ralph H.} and Anirban Maitra and Iacobuzio-Donahue, {Christine A.} and Schulick, {Richard D.} and Wolfgang, {Christopher L.} and Morgan, {Richard A.} and Mary Hodgin and Aldo Scarpa and Lawlor, {Rita T.} and Stefania Beghelli and Vincenzo Corbo and Maria Scardoni and Claudio Bassi and Tempero, {Margaret A.} and Graham, {Janet S.} and Amber Johns and Marina Pajic and Froeling, {Fieke E. M.} and Phillip Beer and Musgrove, {Elizabeth A.} and Petersen, {Gloria M.} and Alan Ashworth and Frame, {Margaret C.} and Crawford, {Howard C.} and Simeone, {Diane M.} and Chris Lord and Debabrata Mukhopadhyay and Christian Pilarsky and Tuveson, {David A.} and Cooke, {Susanna L.} and Jamieson, {Nigel B.} and Morton, {Jennifer P.} and Sansom, {Owen J.} and Bailey, {Peter J.} and Biankin, {Andrew V.} and Chang, {David K.}",

note = "Copyright the AGA Institute 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2021",

month = jan,

doi = "10.1053/j.gastro.2020.09.043",

language = "English",

volume = "160",

pages = "362--377",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W. B. Saunders",

number = "1",

}

Dreyer, SB, Upstill-Goddard, R, Paulus-Hock, V, Paris, C, Lampraki, EM, 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, DW, Duthie, F, Oien, K, Evers, L, McKay, CJ, McGregor, GA, Gulati, A, Brough, R, Bajrami, I, Pettitt, S, Dziubinski, ML, Candido, J, Balkwill, F, Barry, ST, Grützmann, R, Rahib, L, Glasgow Precision Oncology Laboratory, Australian Pancreatic Cancer Genome Initiative, Johns, A, Pajic, M, Froeling, FEM, Beer, P, Musgrove, EA, Petersen, GM, Ashworth, A, Frame, MC, Crawford, HC, Simeone, DM, Lord, C, Mukhopadhyay, D, Pilarsky, C, Tuveson, DA, Cooke, SL, Jamieson, NB, Morton, JP, Sansom, OJ, Bailey, PJ, Biankin, AV & Chang, DK 2021, 'Targeting DNA damage response and replication stress in pancreatic cancer', Gastroenterology, vol. 160, no. 1, pp. 362-377. https://doi.org/10.1053/j.gastro.2020.09.043

TY - JOUR

T1 - Targeting DNA damage response and replication stress in pancreatic cancer

AU - Dreyer, Stephan B.

AU - Upstill-Goddard, Rosie

AU - Paulus-Hock, Viola

AU - Paris, Clara

AU - Lampraki, Eirini Maria

AU - Dray, Eloise

AU - Serrels, Bryan

AU - Caligiuri, Giuseppina

AU - Rebus, Selma

AU - Plenker, Dennis

AU - Galluzzo, Zachary

AU - Brunton, Holly

AU - Cunningham, Richard

AU - Tesson, Mathias

AU - Nourse, Craig

AU - Bailey, Ulla-Maja

AU - Jones, Marc

AU - Moran-Jones, Kim

AU - Wright, Derek W.

AU - Duthie, Fraser

AU - Oien, Karin

AU - Evers, Lisa

AU - McKay, Colin J.

AU - McGregor, Grant A.

AU - Gulati, Aditi

AU - Brough, Rachel

AU - Bajrami, Ilirjana

AU - Pettitt, Stephan

AU - Dziubinski, Michele L.

AU - Candido, Juliana

AU - Balkwill, Frances

AU - Barry, Simon T.

AU - Grützmann, Robert

AU - Rahib, Lola

AU - Glasgow Precision Oncology Laboratory

AU - Allison, Sarah

AU - Beraldi, Dario

AU - Cameron, Euan

AU - Grimwood, Paul

AU - Kelly, Shane

AU - Marshall, John

AU - Martin, Sancha

AU - McDade, Brian

AU - McElroy, Daniel

AU - Ramsay, Donna

AU - Hair, Jane

AU - Westwood, Paul

AU - Williams, Nicola

AU - Australian Pancreatic Cancer Genome Initiative

AU - Mawson, Amanda

AU - Scarlett, Christopher J.

AU - Brancato, Mary-Anne L.

AU - Rowe, Sarah J.

AU - Simpson, Skye H.

AU - Martyn-Smith, Mona

AU - Thomas, Michelle T.

AU - Chantrill, Lorraine A.

AU - Chin, Venessa T.

AU - Chou, Angela

AU - Cowley, Mark J.

AU - Humphris, Jeremy L.

AU - Mead, R. Scott

AU - Nagrial, Adnan M.

AU - Pettit, Jessica

AU - Pinese, Mark

AU - Rooman, Ilse

AU - Wu, Jianmin

AU - Tao, Jiang

AU - DiPietro, Renee

AU - Watson, Clare

AU - Steinmann, Angela

AU - Lee, Hong Ching

AU - Wong, Rachel

AU - Pinho, Andreia V.

AU - Giry-Laterriere, Marc

AU - Daly, Roger J.

AU - Sutherland, Robert L.

AU - Grimmond, Sean M.

AU - Waddell, Nicola

AU - Kassahn, Karin S.

AU - Miller, David K.

AU - Wilson, Peter J.

AU - Patch, Ann Marie

AU - Song, Sarah

AU - Harliwong, Ivon

AU - Idrisoglu, Senel

AU - Nourbakhsh, Ehsan

AU - Manning, Suzanne

AU - Wani, Shivangi

AU - Gongora, Milena

AU - Anderson, Matthew

AU - Holmes, Oliver

AU - Leonard, Conrad

AU - Taylor, Darrin

AU - Wood, Scott

AU - Xu, Christina

AU - Nones, Katia

AU - Fink, J. Lynn

AU - Christ, Angelika

AU - Bruxner, Tim

AU - Cloonan, Nicole

AU - Newell, Felicity

AU - Pearson, John V.

AU - Quinn, Michael

AU - Nagaraj, Shivashankar

AU - Kazakoff, Stephen

AU - Waddell, Nick

AU - Krisnan, Keerthana

AU - Quek, Kelly

AU - Wood, David

AU - Samra, Jaswinder S.

AU - Gill, Anthony J.

AU - Pavlakis, Nick

AU - Guminski, Alex

AU - Toon, Christopher

AU - Asghari, Ray

AU - Merrett, Neil D.

AU - Pavey, Darren

AU - Das, Amitabha

AU - Cosman, Peter H.

AU - Ismail, Kasim

AU - O'Connnor, Chelsie

AU - Lam, Vincent W.

AU - McLeod, Duncan

AU - Pleass, Henry C.

AU - Richardson, Arthur

AU - James, Virginia

AU - Kench, James G.

AU - Cooper, Caroline L.

AU - Joseph, David

AU - Sandroussi, Charbel

AU - Crawford, Michael

AU - Gallagher, James

AU - Texler, Michael

AU - Forest, Cindy

AU - Laycock, Andrew

AU - Epari, Krishna P.

AU - Ballal, Mo

AU - Fletcher, David R.

AU - Mukhedkar, Sanjay

AU - Spry, Nigel A.

AU - DeBoer, Bastiaan

AU - Chai, Ming

AU - Zeps, Nikolajs

AU - Beilin, Maria

AU - Feeney, Kynan

AU - Nguyen, Nan Q.

AU - Ruszkiewicz, Andrew R.

AU - Worthley, Chris

AU - Tan, Chuan P.

AU - Debrencini, Tamara

AU - Chen, John

AU - Brooke-Smith, Mark E.

AU - Papangelis, Virginia

AU - Tang, Henry

AU - Barbour, Andrew P.

AU - Clouston, Andrew D.

AU - Martin, Patrick

AU - O'Rourke, Thomas J.

AU - Chiang, Amy

AU - Fawcett, Jonathan W.

AU - Slater, Kellee

AU - Yeung, Shinn

AU - Hatzifotis, Michael

AU - Hodgkinson, Peter

AU - Christophi, Christopher

AU - Nikfarjam, Mehrdad

AU - Mountain, Angela

AU - Biobank, Victorian Cancer

AU - Eshleman, James R.

AU - Hruban, Ralph H.

AU - Maitra, Anirban

AU - Iacobuzio-Donahue, Christine A.

AU - Schulick, Richard D.

AU - Wolfgang, Christopher L.

AU - Morgan, Richard A.

AU - Hodgin, Mary

AU - Scarpa, Aldo

AU - Lawlor, Rita T.

AU - Beghelli, Stefania

AU - Corbo, Vincenzo

AU - Scardoni, Maria

AU - Bassi, Claudio

AU - Tempero, Margaret A.

AU - Graham, Janet S.

AU - Johns, Amber

AU - Pajic, Marina

AU - Froeling, Fieke E. M.

AU - Beer, Phillip

AU - Musgrove, Elizabeth A.

AU - Petersen, Gloria M.

AU - Ashworth, Alan

AU - Frame, Margaret C.

AU - Crawford, Howard C.

AU - Simeone, Diane M.

AU - Lord, Chris

AU - Mukhopadhyay, Debabrata

AU - Pilarsky, Christian

AU - Tuveson, David A.

AU - Cooke, Susanna L.

AU - Jamieson, Nigel B.

AU - Morton, Jennifer P.

AU - Sansom, Owen J.

AU - Bailey, Peter J.

AU - Biankin, Andrew V.

AU - Chang, David K.

N1 - Copyright the AGA Institute 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2021/1

Y1 - 2021/1

N2 - 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.

AB - 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.

KW - DNA Damage Response

KW - Pancreatic Cancer

KW - Personalized Medicine

KW - Replication Stress

UR - http://www.scopus.com/inward/record.url?scp=85097475066&partnerID=8YFLogxK

UR - http://purl.org/au-research/grants/nhmrc/631701

UR - http://purl.org/au-research/grants/nhmrc/535903

UR - http://purl.org/au-research/grants/nhmrc/427601

U2 - 10.1053/j.gastro.2020.09.043

DO - 10.1053/j.gastro.2020.09.043

M3 - Article

C2 - 33039466

AN - SCOPUS:85097475066

SN - 0016-5085

VL - 160

SP - 362

EP - 377

JO - Gastroenterology

JF - Gastroenterology

IS - 1

ER -

Targeting DNA damage response and replication stress in pancreatic cancer

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