Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Autor: 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, 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, Sarah Allison, Dario Beraldi, Euan Cameron, Stephan Dreyer, Paul Grimwood, Shane Kelly, John Marshall, Sancha Martin, Brian McDade, Daniel McElroy, Donna Ramsay, Derek Wright, Marc D. Jones, Jane Hair, Paul Westwood, Nicola Williams, Amber L. Johns, Amanda Mawson, Christopher J. Scarlett, Mary-Anne L. Brancato, Sarah J. Rowe, Skye H. Simpson, Mona Martyn-Smith, Michelle T. Thomas, Lorraine A. Chantrill, Venessa T. Chin, Angela Chou, Mark J. Cowley, Jeremy L. Humphris, R. Scott Mead, Adnan M. Nagrial, Jessica Pettit, Mark Pinese, Ilse Rooman, Jianmin Wu, Jiang Tao, Renee DiPietro, Clare Watson, Angela Steinmann, Hong Ching Lee, Rachel Wong, Andreia V. Pinho, Marc Giry-Laterriere, Roger J. Daly, 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, Ehsan Nourbakhsh, Suzanne Manning, Shivangi Wani, Milena Gongora, Matthew Anderson, Oliver Holmes, Conrad Leonard, Darrin Taylor, Scott Wood, Christina Xu, Katia Nones, J. Lynn Fink, Angelika Christ, Tim Bruxner, Nicole Cloonan, Felicity Newell, John V. Pearson, Peter Bailey, Michael Quinn, Shivashankar Nagaraj, Stephen Kazakoff, Nick Waddell, Keerthana Krisnan, Kelly Quek, David Wood, Jaswinder S. Samra, Anthony J. Gill, Nick Pavlakis, Alex Guminski, Christopher Toon, Ray Asghari, Neil D. Merrett, Darren Pavey, Amitabha Das, Peter H. Cosman, Kasim Ismail, Chelsie O’Connnor, Vincent W. Lam, Duncan McLeod, Henry C. Pleass, Arthur Richardson, Virginia James, James G. Kench, Caroline L. Cooper, David Joseph, Charbel Sandroussi, Michael Crawford, James Gallagher, Michael Texler, Cindy Forest, Andrew Laycock, Krishna P. Epari, Mo Ballal, David R. Fletcher, Sanjay Mukhedkar, Nigel A. Spry, Bastiaan DeBoer, Ming Chai, Nikolajs Zeps, Maria Beilin, Kynan Feeney, Nan Q. Nguyen, Andrew R. Ruszkiewicz, Chris Worthley, Chuan P. Tan, Tamara Debrencini, John Chen, Mark E. Brooke-Smith, Virginia Papangelis, Henry 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, Janet S. Graham
Přispěvatelé: Basic (bio-) Medical Sciences
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
HRD
homologous recombination deficiency
DNA Repair
PDAC
pancreatic ductal adenocarcinoma
Cell Culture Techniques
DMSO
dimethyl sulfoxide
Transcriptome
0302 clinical medicine
Molecular Targeted Therapy
SV
structural variation
Original Research
Cancer
PDCL
patient-derived cell line
Gastroenterology
Organoids
PC
pancreatic cancer
oncology
PARP inhibitor
RNAseq
RNA sequencing
030211 gastroenterology & hepatology
DNA Damage Response
ICGC
International Cancer Genome Consortium
DNA Replication
DNA repair
DNA damage
RPPA
reverse-phase protein array
EC50
median effective concentration
MTS
3-(4
5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium
Adenocarcinoma
Biology
DDR
DNA damage response
TOM
topological overlap measure
03 medical and health sciences
Pancreatic Cancer
Cell Line
Tumor
Pancreatic cancer
GO
Gene Ontology
medicine
Humans
PDX
patient-derived xenograft
Hepatology
DNA replication
Personalized Medicine
Replication Stress
medicine.disease
Xenograft Model Antitumor Assays
Pancreatic Neoplasms
body regions
030104 developmental biology
siRNA
small interfering RNA
Cancer research
Full Report: Basic and Translational—Pancreas
HR
homologous recombination
Homologous recombination
Biomarkers
DNA Damage
Zdroj: Dreyer, S B, Upstill-goddard, R, Paulus-hock, V, Paris, C, Lampraki, E, Dray, E, Serrels, B, Caligiuri, G, Rebus, S, Plenker, D, Galluzzo, Z, Brunton, H, Cunningham, R, Tesson, M, Nourse, C, Bailey, U, 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, 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, Chang, D K, Allison, S, Bailey, P J, Bailey, U, Biankin, A V, Beraldi, D, Brunton, H, Caligiuri, G, Cameron, E, Chang, D K, Cooke, S L, Cunningham, R, Dreyer, S, Grimwood, P, Kelly, S, Lampraki, E, Marshall, J, Martin, S, Mcdade, B, Mcelroy, D, Musgrove, E A, Nourse, C, Paulus-hock, V, Ramsay, D, Upstill-goddard, R, Wright, D W, Jones, M D, Evers, L, Rebus, S, Rahib, L, Serrels, B, Hair, J, Jamieson, N B, Mckay, C J, Westwood, P, Williams, N, Duthie, F, Biankin, A V, Johns, A L, Mawson, A, Chang, D K, Scarlett, C J, Brancato, M L, Rowe, S J, Simpson, S H, Martyn-smith, M, Thomas, M T, Chantrill, L A, Chin, V T, Chou, A, Cowley, M J, Humphris, J L, Jones, M D, Mead, R S, Nagrial, A M, Pajic, M, Pettit, J, Pinese, M, Rooman, I, Wu, J, Tao, J, Dipietro, R, Watson, C, Steinmann, A, Lee, H C, Wong, R, Pinho, A V, Giry-laterriere, M, Daly, R J, Musgrove, E A, Sutherland, R L, Grimmond, S M, Waddell, N, Kassahn, K S, Miller, D K, Wilson, P J, Patch, A, Song, S, Harliwong, I, Idrisoglu, S, Nourse, C, Nourbakhsh, E, Manning, S, Wani, S, Gongora, M, Anderson, M, Holmes, O, Leonard, C, Taylor, D, Wood, S, Xu, C, Nones, K, Fink, J L, Christ, A, Bruxner, T, Cloonan, N, Newell, F, Pearson, J V, Bailey, P, Quinn, M, Nagaraj, S, Kazakoff, S, Waddell, N, Krisnan, K, Quek, K, Wood, D, Samra, J S, Gill, A J, Pavlakis, N, Guminski, A, Toon, C, Asghari, R, Merrett, N D, Pavey, D, Das, A, Cosman, P H, Ismail, K, O’connnor, C, Lam, V W, Mcleod, D, Pleass, H C, Richardson, A, James, V, Kench, J G, Cooper, C L, Joseph, D, Sandroussi, C, Crawford, M, Gallagher, J, Texler, M, Forest, C, Laycock, A, Epari, K P, Ballal, M, Fletcher, D R, Mukhedkar, S, Spry, N A, Deboer, B, Chai, M, Zeps, N, Beilin, M, Feeney, K, Nguyen, N Q, Ruszkiewicz, A R, Worthley, C, Tan, C P, Debrencini, T, Chen, J, Brooke-smith, M E, Papangelis, V, Tang, H, Barbour, A P, Clouston, A D, Martin, P, O’rourke, T J, Chiang, A, Fawcett, J W, Slater, K, Yeung, S, Hatzifotis, M, Hodgkinson, P, Christophi, C, Nikfarjam, M, Mountain, A, Biobank, V C, Eshleman, J R, Hruban, R H, Maitra, A, Iacobuzio-donahue, C A, Schulick, R D, Wolfgang, C L, Morgan, R A, Hodgin, M, Scarpa, A, Lawlor, R T, Beghelli, S, Corbo, V, Scardoni, M, Bassi, C, Tempero, M A, Biankin, A V, Grimmond, S M, Chang, D K, Musgrove, E A, Jones, M D, Nourse, C, Jamieson, N B, Graham, J S, Biankin, A V, Chang, D K, Jamieson, N B & Graham, J S 2020, ' Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer ', Gastroenterology, vol. 160, no. 1, pp. 362-377.e13 . https://doi.org/10.1053/j.gastro.2020.09.043
Gastroenterology
DOI: 10.1053/j.gastro.2020.09.043
Popis: 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.
Graphical abstract
Databáze: OpenAIRE
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