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 UM, 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, Allison S, Bailey PJ, Biankin AV, Beraldi D, Cameron E, Chang DK, Cooke SL, Dreyer S, Grimwood P, Kelly S, Marshall J, Martin S, McDade B, McElroy D, Musgrove EA, Ramsay D, Wright D, Jones MD, Hair J, Jamieson NB, Westwood P, Williams N, Johns AL, Mawson A, Scarlett CJ, Brancato MAL, Rowe SJ, Simpson SH, Martyn-Smith M, Thomas MT, Chantrill LA, Chin VT, Chou A, Cowley MJ, Humphris JL, Mead RS, Nagrial AM, Pajic M, Pettit J, Pinese M, Rooman I, Wu J, Tao J, DiPietro R, Watson C, Steinmann A, Lee HC, Wong R, Pinho AV, Giry-Laterriere M, Daly RJ, Sutherland RL, Grimmond SM, Waddell N, Kassahn KS, Miller DK, Wilson PJ, Patch AM, Song S, Harliwong I, Idrisoglu S, Nourbakhsh E, Manning S, Wani S, Gongora M, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu C, Nones K, Fink JL, Christ A, Bruxner T, Cloonan N, Newell F, Pearson JV, Bailey P, Quinn M, Nagaraj S, Kazakoff S, Waddell N, Krisnan K, Quek K, Wood D, Samra JS, Gill AJ, Pavlakis N, Guminski A, Toon C, Asghari R, Merrett ND, Pavey D, Das A, Cosman PH, Ismail K, O'Connnor C, Lam VW, McLeod D, Pleass HC, Richardson A, James V, Kench JG, Cooper CL, Joseph D, Sandroussi C, Crawford M, Gallagher J, Texler M, Forest C, Laycock A, Epari KP, Ballal M, Fletcher DR, Mukhedkar S, Spry NA, DeBoer B, Chai M, Zeps N, Beilin M, Feeney K, Nguyen NQ, Ruszkiewicz AR, Worthley C, Tan CP, Debrencini T, Chen J, Brooke-Smith ME, Papangelis V, Tang H, Barbour AP, Clouston AD, Martin P, O'Rourke TJ, Chiang A, Fawcett JW, Slater K, Yeung S, Hatzifotis M, Hodgkinson P, Christophi C, Nikfarjam M, Mountain A, Biobank VC, Eshleman JR, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Hodgin M, Scarpa A, Lawlor RT, Beghelli S, Corbo V, Scardoni M, Bassi C, Tempero MA, Graham JS, Johns A, Froeling FE, Beer P, Petersen GM, Ashworth A, Frame MC, Crawford HC, Simeone DM, Lord C, Mukhopadhyay D, Pilarsky C, Tuveson DA, Morton JP, Sansom OJ (2021)
Publication Type: Journal article
Publication year: 2021
Book Volume: 160
Pages Range: 362-377.e13
Journal Issue: 1
DOI: 10.1053/j.gastro.2020.09.043
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.
APA:
Dreyer, S.B., Upstill-Goddard, R., Paulus-Hock, V., Paris, C., Lampraki, E.M., Dray, E.,... Sansom, O.J. (2021). Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer. Gastroenterology, 160(1), 362-377.e13. https://dx.doi.org/10.1053/j.gastro.2020.09.043
MLA:
Dreyer, Stephan B., et al. "Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer." Gastroenterology 160.1 (2021): 362-377.e13.
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