The BET Inhibitor JQ1 Augments the Antitumor Efficacy of Gemcitabine in Preclinical Models of Pancreatic Cancer.
The BET Inhibitor JQ1 Augments the Antitumor Efficacy of Gemcitabine in Preclinical Models of Pancreatic Cancer.
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BET 抑制剂 JQ1 增强吉西他滨在胰腺癌临床前模型中的抗肿瘤功效。
DOI：
10.3390/cancers13143470
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发表时间：
2021-07-11
期刊：
影响因子：
5.2
通讯作者：
Yoon KJ
中科院分区：
文献类型：
--
作者：
Miller AL;Garcia PL;Fehling SC;Gamblin TL;Vance RB;Council LN;Chen D;Yang ES;van Waardenburg RCAM;Yoon KJ
BET溴结构域抑制剂JQ1减缓胰腺癌临床前模型的肿瘤生长。然而，作为单一药物，它不会诱导肿瘤消退。我们假设JQ1会使胰腺肿瘤对吉西他滨（一种用于该肿瘤类型患者的药物）敏感。我们评估了JQ1 +吉西他滨在胰腺癌细胞系和两种患者来源的异种移植模型中的疗效。数据显示，JQ1 +吉西他滨在体外具有协同作用，且该组合在体内的疗效优于任何一种药物单独使用。RNA-seq分析表明，JQ1 +吉西他滨选择性抑制支持肿瘤细胞增殖的胆固醇生物合成和脂质代谢所必需的蛋白质的表达。数据表明，BET抑制剂+吉西他滨治疗胰腺癌值得进一步研究。吉西他滨用于治疗胰腺癌（PC），但不能治愈。我们试图确定吉西他滨+ BET溴域抑制剂是否优于吉西他滨，并确定可能有助于这种组合疗效的蛋白质。这项研究是基于观察到细胞周期失调和DNA损伤增加吉西他滨的疗效。BET抑制剂在G1期阻滞细胞，并允许DNA损伤增加，可能是由于DNA修复蛋白Ku80和RAD51的表达受到抑制。BET抑制剂（JQ1或I-BET762） +吉西他滨在体外对Panc1、MiaPaCa2和Su86 PC细胞系具有协同作用。在患者来源的异种移植模型中，JQ1 +吉西他滨比单独使用任何一种药物更有效（P < 0.01）。凋亡标记物cleaved caspase 3和DNA损伤标记物γ - h2ax的增加与抗肿瘤效果平行。值得注意的是，RNA-seq数据显示，与对照组相比，JQ1 +吉西他滨选择性抑制HMGCS2和APOC1约6倍。这些蛋白参与胆固醇的生物合成和脂质代谢，它们的过表达支持肿瘤细胞的增殖。IPA数据显示，JQ1 +吉西他滨选择性抑制LXR/RXR激活途径，这可能是JQ1 +吉西他滨体内疗效观察的原因之一。
The BET bromodomain inhibitor JQ1 slows tumor growth in preclinical models of pancreatic cancer. However, as a single agent, it does not induce tumor regressions. We hypothesized that JQ1 would sensitize pancreatic tumors to gemcitabine, a drug used for patients with this tumor type. We evaluated the efficacy of JQ1 + gemcitabine in pancreatic cancer cell lines and in two patient-derived xenograft models. The data show that JQ1 + gemcitabine is synergistic in vitro and that this combination has greater efficacy than either drug alone in vivo. RNA-seq analyses to identify mechanisms that may contribute to the observed synergy demonstrated that JQ1 + gemcitabine selectively inhibits expression of proteins necessary for cholesterol biosynthesis and lipid metabolism that support tumor cell proliferation. The data indicate that a BET inhibitor + gemcitabine warrants further investigation for the treatment of pancreatic cancer. Gemcitabine is used to treat pancreatic cancer (PC), but is not curative. We sought to determine whether gemcitabine + a BET bromodomain inhibitor was superior to gemcitabine, and identify proteins that may contribute to the efficacy of this combination. This study was based on observations that cell cycle dysregulation and DNA damage augment the efficacy of gemcitabine. BET inhibitors arrest cells in G1 and allow increases in DNA damage, likely due to inhibition of expression of DNA repair proteins Ku80 and RAD51. BET inhibitors (JQ1 or I-BET762) + gemcitabine were synergistic in vitro, in Panc1, MiaPaCa2 and Su86 PC cell lines. JQ1 + gemcitabine was more effective in vivo than either drug alone in patient-derived xenograft models (P < 0.01). Increases in the apoptosis marker cleaved caspase 3 and DNA damage marker γH2AX paralleled antitumor efficacy. Notably, RNA-seq data showed that JQ1 + gemcitabine selectively inhibited HMGCS2 and APOC1 ~6-fold, compared to controls. These proteins contribute to cholesterol biosynthesis and lipid metabolism, and their overexpression supports tumor cell proliferation. IPA data indicated that JQ1 + gemcitabine selectively inhibited the LXR/RXR activation pathway, suggesting the hypothesis that this inhibition may contribute to the observed in vivo efficacy of JQ1 + gemcitabine.
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选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
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影响因子：
4.7
作者：
Cui, Yankang;Miao, Chenkui;Liu, Bianjiang
通讯作者：
Liu, Bianjiang
影响因子：
4.6
作者：
Carpenter, Katherine J.;Valfort, Aurore-Cecile;Flaveny, Colin A.
通讯作者：
Flaveny, Colin A.
影响因子：
6.6
作者：
Kirby, Marie K.;Ramaker, Ryne C.;Myers, Richard M.
通讯作者：
Myers, Richard M.
DOI：
10.1038/nrm3312
发表时间：
2012-03-14
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
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