Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer.
Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer.
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DOI：
10.1053/j.gastro.2020.09.043
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发表时间：
2021-01
期刊：
影响因子：
29.4
通讯作者：
Chang DK
中科院分区：
文献类型：
--
作者：
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;Glasgow Precision Oncology Laboratory,;Australian Pancreatic Cancer Genome Initiative;Johns A;Pajic M;Froeling FEM;Beer P;Musgrove EA;Petersen GM;Ashworth A;Frame MC;Crawford HC;Simeone DM;Lord C;Mukhopadhyay D;Pilarsky C;Tuveson DA;Cooke SL;Jamieson NB;Morton JP;Sansom OJ;Bailey PJ;Biankin AV;Chang DK
胰腺癌（PC）是当今世界上最致命的恶性肿瘤，其死亡率已上升至第二位。本研究旨在探讨PC中DNA损伤反应（DDR）、复制应激和新型治疗反应之间的关系，以开发针对PC中DDR和复制应激的生物标志物驱动的治疗策略。我们询问了61种新型PC患者来源的细胞系的转录组、基因组、蛋白质组和功能特征，以确定针对DDR和复制应激的新型治疗策略。在患者来源的异种移植物和人PC类器官中进行了验证。患者来源的细胞系忠实地概括了胰腺肿瘤的上皮成分，包括先前描述的分子亚型。DDR缺陷的生物标志物，包括同源重组缺陷的新特征，在体外和体内与对铂（P <0.001）和PARP抑制剂治疗（P <0.001）的反应共分离。我们产生了一种新的复制应激特征，预测了细胞系和人类PC类器官对ATR（P < .018）和WEE 1抑制剂（P < .029）治疗的反应。复制应激在PC的鳞状亚型中富集（P <0.001），但与DDR缺陷无关。复制压力和DDR缺陷是相互独立的，为DDR熟练的PC和铂治疗后的治疗创造了机会。
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. 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. 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. Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy.
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影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda
影响因子：
12.3
作者：
Fang H;Gough J
通讯作者：
Gough J
影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
12.3
作者：
Boutros M;Brás LP;Huber W
通讯作者：
Huber W
影响因子：
24.5
作者：
Chou A;Froio D;Nagrial AM;Parkin A;Murphy KJ;Chin VT;Wohl D;Steinmann A;Stark R;Drury A;Walters SN;Vennin C;Burgess A;Pinese M;Chantrill LA;Cowley MJ;Molloy TJ;Australian Pancreatic Cancer Genome Initiative (APGI);Waddell N;Johns A;Grimmond SM;Chang DK;Biankin AV;Sansom OJ;Morton JP;Grey ST;Cox TR;Turchini J;Samra J;Clarke SJ;Timpson P;Gill AJ;Pajic M
通讯作者：
Pajic M