Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

作者：Stephan B. Dreyer, Rosanna Upstill‐Goddard, Viola Paulus-Hock, Clara Paris, Eirini-Maria Lampraki, Eloïse Dray, Bryan Serrels, Giuseppina Caligiuri, Selma Rebus, Dennis Plenker, Zachary Galluzzo, Holly Brunton, Richard Cunningham, Mathias Tesson, Craig Nourse, Ulla‐Maja Bailey, Marc D. Jones, Kim Moran‐Jones, Derek Wright, Fraser R. Duthie, Karin A. Oien, Lisa Evers, Colin J. McKay, Grant A. McGregor, Aditi Gulati, Rachel Brough, Ilirjana Bajrami, Stephan Pettitt, Michele L. Dziubinski, Juliana Candido, Frances R. Balkwill, Simon T. Barry, Robert Grützmann, Lola Rahib, Sarah Allison, Peter J. Bailey, Ulla‐Maja Bailey, Andrew V. Biankin, Dario Beraldi, Holly Brunton, Giuseppina Caligiuri, Euan Cameron, David K. Chang, Susanna L. Cooke, Richard Cunningham, Stephan B. Dreyer, Paul Grimwood, Shane Kelly, Eirini-Maria Lampraki, John L. Marshall, Sancha Martin, Brian McDade, Daniel L. McElroy, Elizabeth A. Musgrove, Craig Nourse, Viola Paulus-Hock, Donna Ramsay, Rosie Upstill-Goddard, Derek Wright, Marc D. Jones, Lisa Evers, Selma Rebus, Lola Rahib, Bryan Serrels, Jane Hair, Nigel B. Jamieson, Colin J. McKay, Paul Westwood, Nicola Williams, Fraser Duthie, Andrew V. Biankin, Amber L. Johns, Amanda Mawson, David K. Chang, Christopher J. Scarlett, Mary-Anne L. Brancato, Sarah J. Rowe, Skye H. Simpson, Mona Martyn-Smith, Michelle T. Thomas, Lorraine A. Chantrill, Venessa Chin, Angela Chou, Mark J. Cowley, Jeremy L. Humphris, Marc D. Jones, R. Scott Mead, Adnan M. Nagrial, Marina Pajic, Jessica Pettit, Mark Pinese, Ilse Rooman, Jianmin Wu, Tao Jiang, Renee DiPietro, Clare Watson, Angela Steinmann, Hong Ching Lee, Rachel Wong, Andreia V. Pinho, Marc Giry-Laterrière, Roger J. Daly, Elizabeth A. Musgrove, Robert L. Sutherland, Sean M. Grimmond, Nicola Waddell, Karin S. Kassahn, David K. Miller, Peter J. Wilson, Ann-Marie Patch, Sarah Song, Ivon Harliwong, Senel Idrisoglu, Craig Nourse, Ehsan Nourbakhsh, Suzanne Manning, Shivangi Wani, Milena Gongora, Matthew J. Anderson, Oliver Holmes, Conrad Leonard, Darrin F. Taylor, Scott Wood, Christina Xu, Kátia Nones, J. Lynn Fink, Angelika N. Christ, Tim Bruxner, Nicole Cloonan, Felicity Newell, John V. Pearson, Peter J. Bailey, Michael C. Quinn, Shivashankar H. Nagaraj, Stephen H. Kazakoff, 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, Peter H. Cosman, Kasim Ismail, Chelsie O’Connnor, Vincent Lam, Duncan McLeod, Henry Pleass, A. J. Richardson, Virginia James, James G. Kench, Caroline Cooper, David Joseph, Charbel Sandroussi, Michael Crawford, James Gallagher, Michael Texler, Cindy Forest, Andrew Laycock, Krishna Epari, Mo Ballal, David Fletcher, Sanjay Mukhedkar, Nigel Spry, Bastiaan DeBoer, Ming G. Chai, Nikolajs Zeps, Maria Beilin, Kynan Feeney, Nan Q. Nguyen, Andrew Ruszkiewicz, Chris Worthley, Chuan Tan, Tamara Debrencini, John Chen, Mark E. Brooke‐Smith, Virginia Papangelis, Henry H. K. Tang, Andrew P. Barbour, Andrew D. Clouston, Patrick Martin, Thomas J. O’Rourke, Amy Chiang, Jonathan W. Fawcett, Kellee Slater, Shinn Yeung, Michael Hatzifotis, Peter Hodgkinson, Christopher Christophi, Mehrdad Nikfarjam, Angela Mountain, Victorian Cancer Biobank, James R. Eshleman, Ralph H. Hruban, Anirban Maitra, Christine A. Iacobuzio–Donahue, 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, Sean M. Grimmond, David K. Chang, Elizabeth A. Musgrove, Marc D. Jones, Craig Nourse, Nigel B. Jamieson, Janet S. Graham, Andrew V. Biankin, David K. Chang, Nigel B. Jamieson, Janet S. Graham, Amber L. 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 · 发表于：Gastroenterology · 年份：2020 · DOI：10.1053/j.gastro.2020.09.043 · 被引用次数：176 · 研究领域：DNA Repair Mechanisms、PARP inhibition in cancer therapy、Cancer therapeutics and mechanisms

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 D...