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Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer
- Source :
- 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
- Publication Year :
- 2021
-
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.<br />Graphical abstract
- Subjects :
- 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
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- 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
- Accession number :
- edsair.doi.dedup.....73a3f9673fbfb1bdd5184962a42fdfee
- Full Text :
- https://doi.org/10.1053/j.gastro.2020.09.043