Lin Tzu-Yin, Bear Misty, Du Zhenjian, Foley Kevin P, Ying Weiwen, Barsoum James, London Cheryl
Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
Exp Hematol. 2008 Oct;36(10):1266-77. doi: 10.1016/j.exphem.2008.05.001. Epub 2008 Jul 26.
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.
受体酪氨酸激酶Kit的突变存在于多种人类和犬类癌症中。虽然Kit抑制剂在临床环境中有活性，但它们对特定形式的突变Kit的疗效各不相同，且耐药性通常会随着时间的推移而产生。热休克蛋白90（HSP90）的抑制剂，而Kit是该伴侣蛋白的底物蛋白，已证明对人类癌症有活性，且有证据表明它们可下调几种突变的和对伊马替尼耐药的Kit形式。本研究的目的是评估一种新型HSP90抑制剂STA-9090对犬骨髓来源的培养肥大细胞（BMCMC）、恶性肥大细胞系和新鲜恶性肥大细胞中的野生型（WT）和突变型Kit的作用。
用STA-9090、17-AAG和SU11654处理BMCMC、细胞系和新鲜恶性肥大细胞，并评估细胞活力丧失、细胞死亡、HSP90和Kit表达/信号传导的改变以及Kit突变情况。在犬肥大细胞瘤异种移植模型中测试STA-9090的活性。
用STA-9090处理BMCMC、细胞系和新鲜恶性细胞可诱导生长抑制、依赖半胱天冬酶-3/7的凋亡，以及磷酸化/总Kit和Akt的下调，但不影响细胞外信号调节激酶（ERK）或磷酸肌醇-3激酶（PI-3K）。还观察到Kit细胞表面表达的丧失。此外，STA-9090表现出比17-AAG和SU11654更强的活性，并且对表达WT或突变型Kit的恶性肥大细胞有效。最后，STA-9090在犬肥大细胞瘤小鼠异种移植模型中抑制了肿瘤生长。
STA-9090对表达WT或突变型Kit的肥大细胞具有广泛活性，表明它可能是临床上对抗肥大细胞恶性肿瘤的有效药物。
