The novel HSP90 inhibitor STA-9090 exhibits activity against Kit-dependent and -independent malignant mast cell tumors.
The novel HSP90 inhibitor STA-9090 exhibits activity against Kit-dependent and -independent malignant mast cell tumors.
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DOI：
10.1016/j.exphem.2008.05.001
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发表时间：
2008-10
影响因子：
2.6
通讯作者：
London, Cheryl
中科院分区：
文献类型：
--
作者：
Lin, Tzu-Yin;Bear, Misty;Du, Zhenjian;Foley, Kevin P.;Ying, Weiwen;Barsoum, James;London, Cheryl
受体酪氨酸激酶Kit的突变发生在几种人类和犬的癌症中。虽然Kit抑制剂在临床环境中具有活性，但它们对特定形式的突变Kit具有可变的功效，并且耐药性通常随着时间的推移而发展。热休克蛋白90（HSP 90）（Kit是其客户蛋白的伴侣蛋白）的抑制剂已显示出对人类癌症的活性，并且有证据表明它们下调Kit的几种突变和伊马替尼抗性形式。本研究的目的是评估一种新型的热休克蛋白90抑制剂，STA-9090，对野生型（WT）和突变型试剂盒在犬骨髓来源的培养肥大细胞（BMCMCCs），恶性肥大细胞系，和新鲜的恶性肥大细胞。用STA-9090、17-AAG和SU 11654处理BMCMC、细胞系和新鲜恶性肥大细胞，并评价细胞活力的丧失、细胞死亡、HSP 90和Kit表达/信号传导的改变以及Kit突变。在犬肥大细胞瘤异种移植模型中测试STA-9090活性。用STA-9090处理BMCMC、细胞系和新鲜恶性细胞诱导生长抑制、半胱天冬酶-3/7依赖性的凋亡以及磷酸化/总Kit和Akt的下调，但不诱导细胞外信号调节激酶（ERK）或磷酸肌醇-3激酶（PI-3 K）。还观察到Kit细胞表面表达的丧失。此外，STA-9090表现出优于17-AAG和SU 11654的活性，并且对表达WT或突变Kit的恶性肥大细胞有效。最后，STA-9090抑制犬肥大细胞瘤小鼠异种移植模型中的肿瘤生长。STA-9090对表达WT或突变Kit的肥大细胞表现出广泛的活性，表明其可能是临床环境中针对肥大细胞恶性肿瘤的有效药剂。
Mutations of the receptor tyrosine kinase Kit occur in several human and canine cancers. While Kit inhibitors have activity in the clinical setting, they possess variable efficacy against particular forms of mutant Kit and drug resistance often develops over time. Inhibitors of heat shock protein 90 (HSP90), a chaperone for which Kit is a client protein, have demonstrated activity against human cancers and evidence suggests they downregulate several mutated and imatinib-resistant forms of Kit. The purpose of this study was to evaluate a novel HSP90 inhibitor, STA-9090, against wild-type (WT) and mutant Kit in canine bone marrow–derived cultured mast cells (BMCMCs), malignant mast cell lines, and fresh malignant mast cells. BMCMCs, cell lines, and fresh malignant mast cells were treated with STA-9090, 17-AAG, and SU11654 and evaluated for loss in cell viability, cell death, alterations in HSP90 and Kit expression/signaling, and Kit mutation. STA-9090 activity was tested in a canine mastocytoma xenograft model. Treatment of BMCMCs, cell lines, and fresh malignant cells with STA-9090 induced growth inhibition, apoptosis that was caspase-3/7–dependent, and downregulation of phospho/total Kit and Akt, but not extracellular signal-regulated kinase (ERK) or phosphoinositide-3 kinase (PI-3K). Loss of Kit cell-surface expression was also observed. Furthermore, STA-9090 exhibited superior activity to 17-AAG and SU11654, and was effective against malignant mast cells expressing either WT or mutant Kit. Lastly, STA-9090 inhibited tumor growth in a canine mastocytoma mouse xenograft model. STA-9090 exhibits broad activity against mast cells expressing WT or mutant Kit, suggesting it may be an effective agent in the clinical setting against mast cell malignancies.
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影响因子：
11.5
作者：
Francis, Lanie K.;Alsayed, Yazan;Ghobrial, Irene M.
通讯作者：
Ghobrial, Irene M.
影响因子：
3.4
作者：
Ronnen, Ellen A.;Kondagunta, G. Varuni;Motzer, Robert J.
通讯作者：
Motzer, Robert J.
DOI：
10.1007/s10120-006-0368-5
发表时间：
2006-01-01
期刊：
Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association
影响因子：
--
作者：
Koyama, Tomoki;Nimura, Hiroshi;Yanaga, Katsuhiko
通讯作者：
Yanaga, Katsuhiko
影响因子：
20.3
作者：
Akin, C;Fumo, G;Metcalfe, DD
通讯作者：
Metcalfe, DD
影响因子：
2.8
作者：
de Silva, MV;Reid, R
通讯作者：
Reid, R