Pan-mTOR inhibitor MLN0128 is effective against intrahepatic cholangiocarcinoma in mice.
Pan-mTOR inhibitor MLN0128 is effective against intrahepatic cholangiocarcinoma in mice.
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Pan-mTOR抑制剂MLN0128对小鼠肝内胆管癌有效
DOI：
10.1016/j.jhep.2017.07.006
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发表时间：
2017-12
影响因子：
25.7
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Zhang S;Song X;Cao D;Xu Z;Fan B;Che L;Hu J;Chen B;Dong M;Pilo MG;Cigliano A;Evert K;Ribback S;Dombrowski F;Pascale RM;Cossu A;Vidili G;Porcu A;Simile MM;Pes GM;Giannelli G;Gordan J;Wei L;Evert M;Cong W;Calvisi DF;Chen X
肝内胆管细胞癌（ICC）是一种致命的恶性肿瘤，没有有效的治疗方案。MLN 0128是第二代pan-mTOR抑制剂，对多种肿瘤类型显示出疗效。我们通过AKT（myr-AKT）和雅普（YapS 127 A）原癌基因的活化形式（将被称为AKT/YapS 127 A）的流体动力学转染建立了新的ICC小鼠模型。应用遗传学方法研究mTORC 1和mTORC 2在介导AKT/YapS 127 A驱动的肿瘤发生中的需求。在AKT/YapS 127 A荷瘤小鼠中给予吉西他滨/奥沙利铂和MLN 0128，以研究其体内抗肿瘤疗效。多种人ICC细胞系用于体外实验。采用苏木素和伊红染色、免疫组织化学和免疫印迹进行表征和机制研究。myr-AKT和YapS 127 A的共表达促进小鼠ICC的发育。AKT/YapS 127 A ICC的形成需要mTORC 1和mTORC 2复合物。吉西他滨/奥沙利铂治疗晚期AKT/YapS 127 A ICC的疗效有限。相比之下，在AKT/YapS 127 A胆管癌发生的晚期阶段应用MLN 0128时，实现了部分肿瘤消退。此外，当在AKT/YapS 127 A致癌早期给予MLN 0128时，其导致疾病稳定。从机制上讲，MLN 0128在体内和体外均有效抑制AKT/mTOR信号传导，诱导强烈的ICC细胞凋亡，仅轻微影响增殖。总之，我们的研究表明，mTOR激酶抑制剂可能有益于ICC的治疗，即使在对标准化疗药物如基于吉西他滨/奥沙利铂的方案具有抗性的肿瘤中，特别是在表现出活化的AKT/mTOR级联的亚组中。我们建立了一种新的小鼠肝内胆管癌（ICC）模型。使用这种新的临床前模型，我们评估了mTOR抑制剂MLN 0128与吉西他滨/奥沙利铂（ICC治疗的标准化疗）的治疗潜力。我们的研究显示了MLN 0128的抗肿瘤潜力，这表明它在治疗ICC方面可能优于基于吉西他滨/奥沙利铂的化疗，特别是在表现出激活的AKT/mTOR级联反应的肿瘤中。上级。
Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy without effective treatment options. MLN0128, a second-generation pan-mTOR inhibitor, shows efficacy for multiple tumor types. We established a novel ICC mouse model via hydrodynamic transfection of activated forms of AKT (myr-AKT) and Yap (YapS127A) protooncogenes (that will be referred to as AKT/YapS127A). Genetic approaches were applied to study the requirement of mTORC1 and mTORC2 in mediating AKT/YapS127A driven tumorigenesis. Gemcitabine/Oxaliplatin and MLN0128 were administered in AKT/YapS127A tumor-bearing mice to study their antitumor efficacy in vivo. Multiple human ICC cell lines were used for in vitro experiments. Hematoxylin and eosin staining, immunohistochemistry and immunoblotting were applied for characterization and mechanistic study. Co-expression of myr-AKT and YapS127A promoted ICC development in mice. Both mTORC1 and mTORC2 complexes were required for AKT/YapS127A ICC development. Gemcitabine/Oxaliplatin had limited efficacy in treating late stage AKT/YapS127A ICC. In contrast, partial tumor regression was achieved when MLN0128 was applied in the late stage of AKT/YapS127A cholangiocarcinogenesis. Furthermore, when MLN0128 was administered in the early stage of AKT/YapS127A carcinogenesis, it led to disease stabilization. Mechanistically, MLN0128 efficiently inhibited AKT/mTOR signaling both in vivo and in vitro, inducing strong ICC cell apoptosis and only marginally affecting proliferation. Altogether, our study suggests that mTOR kinase inhibitors may be beneficial for the treatment of ICC, even in tumors that are resistant to standard of care chemotherapeutics such as gemcitabine/Oxaliplatin based regimen, especially in the subset exhibiting activated AKT/mTOR cascade. We established a novel mouse model of intrahepatic cholangiocarcinoma (ICC). Using this new preclinical model, we evaluated the therapeutic potential of mTOR inhibitor MLN0128 versus Gemcitabine/Oxaliplatin (the standard chemotherapy for ICC treatment). Our study shows the anti-neoplastic potential of MLN0128, suggesting that it may be superior to Gemcitabine/Oxaliplatin based chemotherapy for the treatment of ICC, especially in the tumors exhibiting activated AKT/mTOR cascade.
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影响因子：
13.5
作者：
Wang, Chunmei;Cigliano, Antonio;Jiang, Lijie;Li, Xiaolei;Fan, Biao;Pilo, Maria G.;Liu, Yan;Gui, Bing;Sini, Marcella;Smith, Jeffrey W.;Dombrowski, Frank;Calvisi, Diego F.;Evert, Matthias;Chen, Xin
通讯作者：
Chen, Xin
影响因子：
64.8
作者：
Hsieh, Andrew C.;Liu, Yi;Edlind, Merritt P.;Ingolia, Nicholas T.;Janes, Matthew R.;Sher, Annie;Shi, Evan Y.;Stumpf, Craig R.;Christensen, Carly;Bonham, Michael J.;Wang, Shunyou;Ren, Pingda;Martin, Michael;Jessen, Katti;Feldman, Morris E.;Weissman, Jonathan S.;Shokat, Kevan M.;Rommel, Christian;Ruggero, Davide
通讯作者：
Ruggero, Davide
DOI：
10.6004/jnccn.2014.0112
发表时间：
2014-08-01
影响因子：
13.4
作者：
Benson, Al B.;D'Angelica, Michael I.;Sundar, Hema
通讯作者：
Sundar, Hema
影响因子：
4.3
作者：
Schmitz, K. J.;Lang, H.;Baba, H. A.
通讯作者：
Baba, H. A.
影响因子：
7.2
作者：
Gardner, Brooke M.;Pincus, David;Walter, Peter
通讯作者：
Walter, Peter