Kinase profiling of liposarcomas using RNAi and drug screening assays identified druggable targets.
Kinase profiling of liposarcomas using RNAi and drug screening assays identified druggable targets.
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DOI：
10.1186/s13045-017-0540-x
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发表时间：
2017-11-13
影响因子：
28.5
通讯作者：
Koeffler HP
中科院分区：
文献类型：
--
作者：
Kanojia D;Garg M;Martinez J;M T A;Luty SB;Doan NB;Said JW;Forscher C;Tyner JW;Koeffler HP
脂肪肉瘤是最常见的软组织肿瘤，是一种研究较少的肿瘤，在转移性疾病的治疗方面进展有限。癌症的致命弱点往往是它们的激酶是很好的治疗靶点。然而，对于脂肪肉瘤中可能用于疾病治疗的治疗关键激酶靶点的了解非常有限。对不同亚型脂肪肉瘤细胞系的增殖能力进行了大RNAi和小分子酪氨酸激酶抑制剂筛选。每一种小分子抑制剂要么得到FDA的批准，要么正在进行临床试验。筛选试验确定了几个以前未被识别的靶点，包括脂肪肉瘤中的PTK2和KIT。我们还观察到，多靶点酪氨酸激酶抑制剂Ponatinib是对所有细胞株都有抑制生长作用的最有效的药物。体外实验表明，Ponatinib抑制脂肪肉瘤的克隆性增殖，这种抑制生长作用与细胞凋亡和细胞周期停滞于G0/G1期以及KIT信号通路的减少有关。此外，在异种移植模型中，波纳替尼抑制脂肪肉瘤的体内生长。两项大规模的激酶筛查发现了新的脂肪肉瘤靶点和FDA批准的具有明显抗脂肉瘤活性的抑制剂庞纳替尼，突显了其治疗这种致命肿瘤的潜在疗法。本文的在线版本(10.1186/s130450170540x)包含补充材料，可供授权用户使用。
Liposarcoma, the most common soft tissue tumor, is understudied cancer, and limited progress has been made in the treatment of metastatic disease. The Achilles heel of cancer often is their kinases that are excellent therapeutic targets. However, very limited knowledge exists of therapeutic critical kinase targets in liposarcoma that could be potentially used in disease management. Large RNAi and small-molecule tyrosine kinase inhibitor screens were performed against the proliferative capacity of liposarcoma cell lines of different subtypes. Each small molecule inhibitor was either FDA approved or in a clinical trial. Screening assays identified several previously unrecognized targets including PTK2 and KIT in liposarcoma. We also observed that ponatinib, multi-targeted tyrosine kinase inhibitor, was the most effective drug with anti-growth effects against all cell lines. In vitro assays showed that ponatinib inhibited the clonogenic proliferation of liposarcoma, and this anti-growth effect was associated with apoptosis and cell cycle arrest at the G0/G1 phase as well as a decrease in the KIT signaling pathway. In addition, ponatinib inhibited in vivo growth of liposarcoma in a xenograft model. Two large-scale kinase screenings identified novel liposarcoma targets and a FDA-approved inhibitor, ponatinib with clear anti-liposarcoma activity highlighting its potential therapy for treatment of this deadly tumor. The online version of this article (10.1186/s13045-017-0540-x) contains supplementary material, which is available to authorized users.
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伊马替尼：癌症靶向治疗的突破。
DOI：
10.1155/2014/357027
发表时间：
2014
期刊：
Chemotherapy research and practice
影响因子：
--
作者：
Iqbal N;Iqbal N
通讯作者：
Iqbal N
DOI：
10.1056/nejmoa1502309
发表时间：
2015-08-20
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hyman DM;Puzanov I;Subbiah V;Faris JE;Chau I;Blay JY;Wolf J;Raje NS;Diamond EL;Hollebecque A;Gervais R;Elez-Fernandez ME;Italiano A;Hofheinz RD;Hidalgo M;Chan E;Schuler M;Lasserre SF;Makrutzki M;Sirzen F;Veronese ML;Tabernero J;Baselga J
通讯作者：
Baselga J
影响因子：
6.4
作者：
Mahmood, S. Tariq;Agresta, Samuel;Vigil, Carlos E.;Zhao, Xiuhua;Han, Gang;D'Amato, Gina;Calitri, Ciara E.;Dean, Michelle;Garrett, Christopher;Schell, Michael J.;Antonia, Scott;Chiappori, Alberto
通讯作者：
Chiappori, Alberto
DOI：
10.1056/nejmoa1306494
发表时间：
2013-11-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Cortes JE;Kim DW;Pinilla-Ibarz J;le Coutre P;Paquette R;Chuah C;Nicolini FE;Apperley JF;Khoury HJ;Talpaz M;DiPersio J;DeAngelo DJ;Abruzzese E;Rea D;Baccarani M;Müller MC;Gambacorti-Passerini C;Wong S;Lustgarten S;Rivera VM;Clackson T;Turner CD;Haluska FG;Guilhot F;Deininger MW;Hochhaus A;Hughes T;Goldman JM;Shah NP;Kantarjian H;PACE Investigators
通讯作者：
PACE Investigators
影响因子：
64.8
作者：
Johannessen, Cory M.;Boehm, Jesse S.;Kim, So Young;Thomas, Sapana R.;Wardwell, Leslie;Johnson, Laura A.;Emery, Caroline M.;Stransky, Nicolas;Cogdill, Alexandria P.;Barretina, Jordi;Caponigro, Giordano;Hieronymus, Haley;Murray, Ryan R.;Salehi-Ashtiani, Kourosh;Hill, David E.;Vidal, Marc;Zhao, Jean J.;Yang, Xiaoping;Alkan, Ozan;Kim, Sungjoon;Harris, Jennifer L.;Wilson, Christopher J.;Myer, Vic E.;Finan, Peter M.;Root, David E.;Roberts, Thomas M.;Golub, Todd;Flaherty, Keith T.;Dummer, Reinhard;Weber, Barbara L.;Sellers, William R.;Schlegel, Robert;Wargo, Jennifer A.;Hahn, William C.;Garraway, Levi A.
通讯作者：
Garraway, Levi A.