Replicative stress in gastroesophageal cancer is associated with chromosomal instability and sensitivity to DNA damage response inhibitors.
Replicative stress in gastroesophageal cancer is associated with chromosomal instability and sensitivity to DNA damage response inhibitors.
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DOI：
10.1016/j.isci.2023.108169
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发表时间：
2023-11-17
期刊：
影响因子：
5.8
通讯作者：
Sethi, Nilay S.
中科院分区：
文献类型：
--
作者：
Sahgal, Pranshu;Patil, Deepa T.;Bala, Pratyusha;Sztupinszki, Zsofia M.;Tisza, Viktoria;Spisak, Sandor;Luong, Anna G.;Huffman, Brandon;Prosz, Aurel;Singh, Harshabad;Lazaro, Jean-Bernard;Szallasi, Zoltan;Cleary, James M.;Sethi, Nilay S.
胃食管腺癌（GEA）是一种具有染色体不稳定性（CIN）的侵袭性恶性肿瘤。为了了解DNA损伤反应（DDR）和CIN的适应性反应，我们分析了人类标本和致癌物诱导的小鼠模型中匹配的正常、癌前和恶性胃病变，观察了肿瘤进展中复制应激、DDR和p21的激活。在GEA细胞系中，DDR标记的表达与倍性异常相关，例如高水平局灶性扩增和全基因组复制（WGD）的数量。将TP 53状态、倍性异常和DDR标志物整合到综合评分中有助于预测对Chk 1/2和Wee 1抑制（单独或与伊立替康联合）敏感性增强的GEA细胞系（SN 38）。我们证明，Chk 1/2或Wee 1抑制与SN 38/伊立替康联合在人胃癌类器官和体内异种移植小鼠模型中显示出更大的抗肿瘤活性。这些发现表明，特定的DDR生物标志物和倍性异常可以预测癌前进展和对DDR通路抑制剂的反应。DDR和复制应激在人类和小鼠胃癌前病变中被激活DDR标记物表达与胃癌中较高的倍性异常相关倍性异常累积评分（CSPA）预测DDR抑制剂反应DDR抑制剂伊立替康组合改善胃癌模型中的抗肿瘤作用临床遗传学;肿瘤学;癌症
Gastroesophageal adenocarcinoma (GEA) is an aggressive malignancy with chromosomal instability (CIN). To understand adaptive responses enabling DNA damage response (DDR) and CIN, we analyzed matched normal, premalignant, and malignant gastric lesions from human specimens and a carcinogen-induced mouse model, observing activation of replication stress, DDR, and p21 in neoplastic progression. In GEA cell lines, expression of DDR markers correlated with ploidy abnormalities, such as number of high-level focal amplifications and whole-genome duplication (WGD). Integrating TP53 status, ploidy abnormalities, and DDR markers into a compositive score helped predict GEA cell lines with enhanced sensitivity to Chk1/2 and Wee1 inhibition, either alone or combined with irinotecan (SN38). We demonstrate that Chk1/2 or Wee1 inhibition combined with SN38/irinotecan shows greater anti-tumor activity in human gastric cancer organoids and an in vivo xenograft mouse model. These findings indicate that specific DDR biomarkers and ploidy abnormalities may predict premalignant progression and response to DDR pathway inhibitors. DDR and replication stress are activated in human and mouse gastric preneoplasia DDR markers expression correlates with higher ploidy abnormalities in gastric cancer A cumulative score of ploidy abnormalities (CSPA) predicts DDR inhibitor response DDR inhibitor irinotecan combo improves anti-tumor effect in gastric cancer models Clinical genetics; Oncology; Cancer
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影响因子：
64.8
作者：
Cohen-Sharir Y;McFarland JM;Abdusamad M;Marquis C;Bernhard SV;Kazachkova M;Tang H;Ippolito MR;Laue K;Zerbib J;Malaby HLH;Jones A;Stautmeister LM;Bockaj I;Wardenaar R;Lyons N;Nagaraja A;Bass AJ;Spierings DCJ;Foijer F;Beroukhim R;Santaguida S;Golub TR;Stumpff J;Storchová Z;Ben-David U
通讯作者：
Ben-David U
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
DOI：
10.1016/s1470-2045(20)30180-7
发表时间：
2020-07
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Konstantinopoulos PA;Cheng SC;Wahner Hendrickson AE;Penson RT;Schumer ST;Doyle LA;Lee EK;Kohn EC;Duska LR;Crispens MA;Olawaiye AB;Winer IS;Barroilhet LM;Fu S;McHale MT;Schilder RJ;Färkkilä A;Chowdhury D;Curtis J;Quinn RS;Bowes B;D'Andrea AD;Shapiro GI;Matulonis UA
通讯作者：
Matulonis UA
DOI：
10.1016/j.neo.2017.02.012
发表时间：
2017-05
期刊：
Neoplasia (New York, N.Y.)
影响因子：
--
作者：
Maleki SS;Röcken C
通讯作者：
Röcken C
影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J