HSP90抑制剂克服FLT3/ itd阳性白血病细胞N676K突变的FLT3抑制剂耐药性

Hiraku Ogata, Yosuke Minami
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引用次数: 0

摘要

FLT3突变在急性髓性白血病(AML)中经常被发现。特别是,已知FLT3-ITD是预后不良的一个指标。FLT3抑制剂改善了FLT3突变AML患者的治疗效果。然而,已经报道了几种耐药机制,需要新的临床策略来克服耐药。热休克蛋白(HSP) 90是一种分子伴侣,可介导包括FLT3在内的客户蛋白的正确折叠和功能。在本研究中,我们研究了HSP90抑制剂对FLT3抑制剂耐药的AML细胞的影响。利用MOLM-13(一种携带FLT3- itd的AML细胞系),我们建立了FLT3选择性抑制剂(FI-700)耐药细胞系,其FLT3 N676K突变。HSP90抑制剂(17-AAG)抑制了细胞株的生长,FI-700与17-AAG联合处理具有协同抑制作用。其潜在的机制被认为是:HSP90抑制HSP90与FLT3的关联,从而降低FLT3及其下游信号蛋白的磷酸化,从而诱导FLT3的降解。总之,我们证明了HSP90抑制剂可以抑制FLT3抑制剂抵抗的AML细胞的细胞生长。我们的研究结果表明,HSP90是治疗复发/难治性AML的一个有希望的分子靶点。
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An HSP90 Inhibitor Overcomes FLT3 Inhibitor Resistance in FLT3/ITD-Positive Leukemia Cells with an N676K Mutation
FLT3 mutations are frequently identified in acute myeloid leukemia (AML). In particular, FLT3-ITD is known to be an indicator of a poor prognosis. FLT3 inhibitors have improved the treatment outcomes of AML patients with mutated FLT3. However, several drug-resistance mechanisms have been reported, and new clinical strategies to overcome drug resistance are needed. Heat shock protein (HSP) 90 is a molecular chaperone that mediates the correct folding and functionality of its client proteins, including FLT3. In the present study, we investigated the effects of an HSP90 inhibitor on FLT3 inhibitor-resistant AML cells. Using MOLM-13 (an AML cell line harboring FLT3-ITD), we established FLT3-selective inhibitor (FI-700)-resistant cell lines with an FLT3 N676K mutation. An HSP90 inhibitor (17-AAG) inhibited the growth of the cell lines, and combination treatment with FI-700 and 17-AAG showed synergistic inhibition. The underlying mechanism is thought to be as follows: HSP90 inhibits the association between HSP90 and FLT3, and thus reduces the phosphorylation of FLT3 and its downstream signaling proteins, which induces the consequent degradation of FLT3. In summary, we demonstrated that the HSP90 inhibitor could inhibit the cell growth of FLT3 inhibitor-resistant AML cells. Our results suggest that HSP90 is a promising molecular target in relapsed/refractory AML.
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来源期刊
Journal of International Translational Medicine
Journal of International Translational Medicine MEDICINE, RESEARCH & EXPERIMENTAL-
自引率
0.00%
发文量
317
审稿时长
8 weeks
期刊介绍: Journal of International Translational Medicine (JITM, ISSN 2227-6394), founded in 2012, is an English academic journal published by Journal of International Translational Medicine Co., Ltd and sponsored by International Fderation of Translational Medicine. JITM is an open access journal freely serving to submit, review, publish, read and download full text and quote. JITM is a quarterly publication with the first issue published in March, 2013, and all articles published in English are compiled and edited by professional graphic designers according to the international compiling and editing standard. All members of the JITM Editorial Board are the famous international specialists in the field of translational medicine who come from twenty different countries and areas such as USA, Britain, France, Germany and so on.
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