Inhibition of DNA methyltransferase as a novel therapeutic strategy to overcome acquired resistance to dual PI3K/mTOR inhibitors.
Inhibition of DNA methyltransferase as a novel therapeutic strategy to overcome acquired resistance to dual PI3K/mTOR inhibitors.
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DOI：
10.18632/oncotarget.3016
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发表时间：
2015-03-10
期刊：
影响因子：
--
通讯作者：
Zhu XF
中科院分区：
文献类型：
--
作者：
Qian XJ;Li YT;Yu Y;Yang F;Deng R;Ji J;Jiao L;Li X;Wu RY;Chen WD;Feng GK;Zhu XF
双重PI3K/mTOR(磷脂酰肌醇3-激酶/哺乳动物雷帕霉素靶标)抑制剂正在进行临床评估，用于治疗PI3K/mTOR途径过度激活的肿瘤。然而，在对PI3K通路异常的癌症患者的临床研究中，获得了意想不到的结果。在临床试验中，还没有可用的联合方案。在这项研究中，通过对获得性BEZ235耐药鼻咽癌细胞的综合分析，我们证明了DNA甲基转移酶是一个关键的调节器，也是AKT/mTOR和PDK1/MYC通路上游的一个共同节点，这两个通路在获得性BEZ235耐药癌细胞中被激活。DNA甲基转移酶上调并诱导PTEN和PPP2R2B基因高甲基化，从而下调其在BEZ235耐药癌细胞中的表达。鼻咽癌中PTEN和PPP2R2B的表达降低与AKT/mTOR和PDK1/MYC通路激活有关，并导致对BEZ235的大量耐药。靶向甲基转移酶联合BEZ235在体内外对BEZ235耐药细胞增敏，提示这一策略在克服BEZ235耐药方面具有潜在的临床应用价值。
Dual PI3K/mTOR(phosphatidylinositol 3-kinase/mammalian target of rapamycin) inhibitors are being evaluated clinically for the treatment of tumors with a hyperactivated PI3K/mTOR pathway. However, unexpected outcomes were obtained in clinical studies of cancer patients with an aberrant PI3K pathway. In clinical trials, applicable combination regimens are not yet available. In this study, using an integrated analysis of acquired BEZ235-resistant nasopharyngeal carcinoma cells, we demonstrate that DNA methyltransferase is a key modulator and a common node upstream of the AKT/mTOR and PDK1/MYC pathways, which are activated in cancer cells with acquired BEZ235 resistance. DNA methyltransferases were upregulated and induced PTEN and PPP2R2B gene hypermethylation, which downregulated their expression in BEZ235-resistant cancer cells. Reduced PTEN and PPP2R2B expression correlated with activated AKT/mTOR and PDK1/MYC pathways and conferred considerable BEZ235 resistance in nasopharyngeal carcinoma. Targeting methyltransferases in combination with BEZ235 sensitized BEZ235-resistant cells to BEZ235 in vitro and in vivo, suggesting the potential clinical application of this strategy to overcome BEZ235 resistance.
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影响因子：
50.3
作者：
Junttila, Teemu T.;Akita, Robert W.;Sliwkowski, Mark X.
通讯作者：
Sliwkowski, Mark X.
影响因子：
64.5
作者：
Delmore JE;Issa GC;Lemieux ME;Rahl PB;Shi J;Jacobs HM;Kastritis E;Gilpatrick T;Paranal RM;Qi J;Chesi M;Schinzel AC;McKeown MR;Heffernan TP;Vakoc CR;Bergsagel PL;Ghobrial IM;Richardson PG;Young RA;Hahn WC;Anderson KC;Kung AL;Bradner JE;Mitsiades CS
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Mitsiades CS
影响因子：
50.3
作者：
Carver BS;Chapinski C;Wongvipat J;Hieronymus H;Chen Y;Chandarlapaty S;Arora VK;Le C;Koutcher J;Scher H;Scardino PT;Rosen N;Sawyers CL
通讯作者：
Sawyers CL
影响因子：
--
作者：
Chen MH;Chiang KC;Cheng CT;Huang SC;Chen YY;Chen TW;Yeh TS;Jan YY;Wang HM;Weng JJ;Chang PM;Liu CY;Li CP;Chao Y;Chen MH;Huang CY;Yeh CN
通讯作者：
Yeh CN
影响因子：
5.7
作者：
Fendri, Ali;Khabir, Abdelmajid;Mokdad-Gargouri, Raja
通讯作者：
Mokdad-Gargouri, Raja