Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer
Stephan B. Dreyer(Beatson West of Scotland Cancer Centre), Rosanna Upstill‐Goddard(University of Glasgow), Viola Paulus-Hock(Cancer Research UK Scotland Institute), Clara Paris(Université Grenoble Alpes), Eirini-Maria Lampraki(University of Glasgow), Eloïse Dray(The University of Texas at San Antonio Health Science Center), Bryan Serrels(Edinburgh Cancer Research), Giuseppina Caligiuri(University of Glasgow), Selma Rebus(University of Glasgow), Dennis Plenker(Cold Spring Harbor Laboratory), Zachary Galluzzo(Cold Spring Harbor Laboratory), Holly Brunton(University of Glasgow), Richard Cunningham(University of Glasgow), Mathias Tesson(Cancer Research UK Scotland Institute), Craig Nourse(Cancer Research UK Scotland Institute), Ulla‐Maja Bailey(University of Glasgow), Marc D. Jones(Queen Elizabeth University Hospital), Kim Moran‐Jones(University of Glasgow), Derek Wright(University of Glasgow), Fraser R. Duthie(Queen Elizabeth University Hospital), Karin A. Oien(Queen Elizabeth University Hospital), Lisa Evers(University of Glasgow), Colin J. McKay(Beatson West of Scotland Cancer Centre), Grant A. McGregor(Cancer Research UK Scotland Institute), Aditi Gulati(Institute of Cancer Research), Rachel Brough(Institute of Cancer Research), Ilirjana Bajrami(Institute of Cancer Research), Stephan Pettitt(Institute of Cancer Research), Michele L. Dziubinski(University of Michigan), Juliana Candido(Queen Mary University of London), Frances R. Balkwill(Queen Mary University of London), Simon T. Barry(AstraZeneca (United Kingdom)), Robert Grützmann(Universitätsklinikum Erlangen), Lola Rahib(Pancreatic Cancer Action Network), Sarah Allison(Garvan Institute of Medical Research), Peter J. Bailey(Garvan Institute of Medical Research), Ulla‐Maja Bailey(Lustgarten Foundation), Andrew V. Biankin(Glasgow Royal Infirmary), Dario Beraldi(University of Glasgow), Holly Brunton(Mayo Clinic), Giuseppina Caligiuri(University of California, San Francisco), Euan Cameron(Edinburgh Cancer Research), David K. Chang(University of Michigan), Susanna L. Cooke(NYU Langone Health), Richard Cunningham(Institute of Cancer Research), Stephan B. Dreyer(Beatson West of Scotland Cancer Centre), Paul Grimwood(Universitätsklinikum Erlangen), Shane Kelly(Cold Spring Harbor Laboratory), Eirini-Maria Lampraki(University of Glasgow), John L. Marshall(Glasgow Royal Infirmary), Sancha Martin(Cancer Research UK Scotland Institute), Brian McDade(The University of Texas at San Antonio Health Science Center), Daniel L. McElroy(Cancer Research UK Scotland Institute), Elizabeth A. Musgrove(Glasgow Royal Infirmary), Craig Nourse(Glasgow Royal Infirmary), Viola Paulus-Hock(Cancer Research UK Scotland Institute), Donna Ramsay(Cancer Research UK Scotland Institute), Rosie Upstill-Goddard(University of Glasgow), Derek Wright(Glasgow Royal Infirmary), Marc D. Jones(Queen Elizabeth University Hospital), Lisa Evers(University of Glasgow), Selma Rebus(University of Glasgow), Lola Rahib(Pancreatic Cancer Action Network), Bryan Serrels(Glasgow Royal Infirmary), Jane Hair(University of Glasgow), Nigel B. Jamieson(Beatson West of Scotland Cancer Centre), Colin J. McKay(Beatson West of Scotland Cancer Centre), Paul Westwood(Cancer Research UK Scotland Institute), Nicola Williams, Fraser Duthie(Queen Elizabeth University Hospital), Andrew V. Biankin(Garvan Institute of Medical Research), Amber L. Johns(Garvan Institute of Medical Research), Amanda Mawson, David K. Chang(University of Glasgow), Christopher J. Scarlett(University of Glasgow), Mary-Anne L. Brancato(Cancer Research UK Scotland Institute), Sarah J. Rowe(Cancer Research UK Scotland Institute), Skye H. Simpson, Mona Martyn-Smith(University of Glasgow), Michelle T. Thomas(University of Glasgow), Lorraine A. Chantrill(University of Glasgow), Venessa Chin(University of Glasgow), Angela Chou(University of Glasgow), Mark J. Cowley(Pancreatic Cancer Action Network), Jeremy L. Humphris(Edinburgh Cancer Research), Marc D. Jones(Queen Elizabeth University Hospital), R. Scott Mead(Glasgow Royal Infirmary), Adnan M. Nagrial(Glasgow Royal Infirmary), Marina Pajic(Garvan Institute of Medical Research), Jessica Pettit, Mark Pinese(Queen Elizabeth University Hospital), Ilse Rooman(Glasgow Royal Infirmary), Jianmin Wu(Garvan Institute of Medical Research), Tao Jiang, Renee DiPietro(Glasgow Royal Infirmary), Clare Watson, Angela Steinmann, Hong Ching Lee, Rachel Wong, Andreia V. Pinho, Marc Giry-Laterrière, Roger J. Daly, Elizabeth A. Musgrove(University of Glasgow), Robert L. Sutherland, Sean M. Grimmond, Nicola Waddell, Karin S. Kassahn(University of Glasgow), David K. Miller, Peter J. Wilson, Ann-Marie Patch(Garvan Institute of Medical Research), Sarah Song(Institute of Cancer Research), Ivon Harliwong, Senel Idrisoglu, Craig Nourse(Cancer Research UK Scotland Institute), Ehsan Nourbakhsh, Suzanne Manning, Shivangi Wani, Milena Gongora, Matthew J. Anderson, Oliver Holmes(Institute of Cancer Research), Conrad Leonard, Darrin F. Taylor(Queen Elizabeth University Hospital), Scott Wood, Christina Xu(University of Glasgow), Kátia Nones, J. Lynn Fink, Angelika N. Christ, Tim Bruxner, Nicole Cloonan(Glasgow Royal Infirmary), Felicity Newell(Cancer Research UK Scotland Institute), John V. Pearson, Peter J. Bailey(Cancer Research UK Scotland Institute), Michael C. Quinn, Shivashankar H. Nagaraj, Stephen H. Kazakoff(Cancer Research UK Scotland Institute), Nick M. Waddell, Keerthana Krisnan, Kelly Quek, David Wood, Jaswinder S. Samra, Anthony J. Gill, Nick Pavlakis, Alex Guminski, Christopher W. Toon, Ray Asghari, Neil D. Merrett, Darren Pavey, Amitabha Das(Universitätsklinikum Erlangen), Peter H. Cosman, Kasim Ismail, Chelsie O’Connnor, Vincent Lam, Duncan McLeod(Cancer Research UK Scotland Institute), Henry Pleass, A. J. Richardson, Virginia James, James G. Kench, Caroline Cooper, David Joseph, Charbel Sandroussi(Glasgow Royal Infirmary), Michael Crawford, James Gallagher, Michael Texler, Cindy Forest, Andrew Laycock, Krishna Epari(The University of Texas at San Antonio Health Science Center), Mo Ballal, David Fletcher, Sanjay Mukhedkar, Nigel Spry, Bastiaan DeBoer, Ming G. Chai, Nikolajs Zeps(University of Glasgow), Maria Beilin, Kynan Feeney, Nan Q. Nguyen, Andrew Ruszkiewicz, Chris Worthley, Chuan Tan, Tamara Debrencini(Glasgow Royal Infirmary), John Chen, Mark E. Brooke‐Smith(University of Michigan), Virginia Papangelis, Henry H. K. Tang, Andrew P. Barbour, Andrew D. Clouston(Glasgow Royal Infirmary), Patrick Martin, Thomas J. O’Rourke(Cancer Research UK Scotland Institute), Amy Chiang, Jonathan W. Fawcett, Kellee Slater(Glasgow Royal Infirmary), Shinn Yeung, Michael Hatzifotis, Peter Hodgkinson, Christopher Christophi(University of Glasgow), Mehrdad Nikfarjam, Angela Mountain, Victorian Cancer Biobank, James R. Eshleman(Universitätsklinikum Erlangen), Ralph H. Hruban, Anirban Maitra, Christine A. Iacobuzio–Donahue(Garvan Institute of Medical Research), Richard D. Schulick, Christopher L. Wolfgang, Richard A. Morgan, Mary Hodgin, Aldo Scarpa, Rita T. Lawlor, Stefania Beghelli, Vincenzo Corbo, Maria Scardoni, Claudio Bassi, Margaret A. Tempero, Andrew V. Biankin(Glasgow Royal Infirmary), Sean M. Grimmond(Cancer Research UK Scotland Institute), David K. Chang(University of Glasgow), Elizabeth A. Musgrove(University of Glasgow), Marc D. Jones(Queen Elizabeth University Hospital), Craig Nourse(Cancer Research UK Scotland Institute), Nigel B. Jamieson(Beatson West of Scotland Cancer Centre), Janet S. Graham, Andrew V. Biankin(Glasgow Royal Infirmary), David K. Chang(University of Glasgow), Nigel B. Jamieson(Beatson West of Scotland Cancer Centre), Janet S. Graham, Amber L. Johns(Garvan Institute of Medical Research), Marina Pajic(Garvan Institute of Medical Research), Fieke E. M. Froeling(Lustgarten Foundation), Phillip Beer(Wellcome Sanger Institute), Elizabeth A. Musgrove(University of Glasgow), Gloria M. Petersen(Mayo Clinic), Alan Ashworth(UCSF Helen Diller Family Comprehensive Cancer Center), Margaret C. Frame(Edinburgh Cancer Research), Howard C. Crawford(University of Michigan), Diane M. Simeone(Glasgow Royal Infirmary), Chris Lord(Institute of Cancer Research), Debabrata Mukhopadhyay(Glasgow Royal Infirmary), Christian Pilarsky(Universitätsklinikum Erlangen), David A. Tuveson(Cold Spring Harbor Laboratory), Susanna L. Cooke(Cancer Research UK Scotland Institute), Nigel B. Jamieson(Beatson West of Scotland Cancer Centre), Jennifer P. Morton(Beatson West of Scotland Cancer Centre), Owen J. Sansom(The University of Texas at San Antonio Health Science Center), Peter J. Bailey(Glasgow Royal Infirmary), Andrew V. Biankin(Glasgow Royal Infirmary), David K. Chang(University of Glasgow)
Cited by 171Open Access
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.