Tumor-intrinsic and tumor-extrinsic factors impacting hsp90- targeted therapy.
Tumor-intrinsic and tumor-extrinsic factors impacting hsp90- targeted therapy.
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DOI：
10.2174/156652412803306729
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发表时间：
2012-11-01
影响因子：
2.5
通讯作者：
Trepel JB
中科院分区：
文献类型：
--
作者：
Alarcon SV;Mollapour M;Lee MJ;Tsutsumi S;Lee S;Kim YS;Prince T;Apolo AB;Giaccone G;Xu W;Neckers LM;Trepel JB
1994年，第一个热休克蛋白90（Hsp 90）抑制剂被鉴定，并且据报道Hsp 90是抗癌治疗的靶点。在过去的18年中，已有17种不同的Hsp 90抑制剂进入临床试验，并且小分子Hsp 90抑制剂作为Hsp 90及其客户蛋白在癌症中的作用的探针具有很高的价值。虽然没有Hsp 90抑制剂获得监管批准，但最近Hsp 90抑制剂的临床开发取得了重大进展，并且在过去的一年中，在HER 2阳性乳腺癌和EML 4-ALK阳性非小细胞肺癌中记录了RECIST反应。迄今为止研究的所有临床Hsp 90抑制剂在其靶点上都是特异性的，即它们仅与Hsp 90和两种相关的热休克蛋白结合。然而，热休克蛋白90抑制剂是显着的多效性，导致超过200客户蛋白质的降解和影响关键的多蛋白复合物。此外，直到最近才认识到，Hsp 90抑制剂可以矛盾地引起它们陪伴的蛋白激酶客户的瞬时激活，导致肿瘤和肿瘤微环境中的信号转导和重要生理事件的启动。Hsp 90研究的另一个最新进展领域是Hsp 90本身和Hsp 90共伴侣蛋白的翻译后修饰研究。总之，一幅图片正在出现，其中Hsp 90抑制剂的影响是由肿瘤细胞内和细胞外环境塑造的，并且其中Hsp 90抑制剂在微环境和系统水平上影响肿瘤和宿主。在这里，我们审查肿瘤的内在和外在因素，影响小分子的功效从事热休克蛋白90分子伴侣机器。
In 1994 the first heat shock protein 90 (Hsp90) inhibitor was identified and Hsp90 was reported to be a target for anticancer therapeutics. In the past 18 years there have been 17 distinct Hsp90 inhibitors entered into clinical trial, and the small molecule Hsp90 inhibitors have been highly valuable as probes of the role of Hsp90 and its client proteins in cancer. Although no Hsp90 inhibitor has achieved regulatory approval, recently there has been significant progress in Hsp90 inhibitor clinical development, and in the past year RECIST responses have been documented in HER2-positive breast cancer and EML4-ALK-positive non-small cell lung cancer. All of the clinical Hsp90 inhibitors studied to date are specific in their target, i.e. they bind exclusively to Hsp90 and two related heat shock proteins. However, Hsp90 inhibitors are markedly pleiotropic, causing degradation of over 200 client proteins and impacting critical multiprotein complexes. Furthermore, it has only recently been appreciated that Hsp90 inhibitors can, paradoxically, cause transient activation of the protein kinase clients they are chaperoning, resulting in initiation of signal transduction and significant physiological events in both tumor and tumor microenvironment. An additional area of recent progress in Hsp90 research is in studies of the posttranslational modifications of Hsp90 itself and Hsp90 co-chaperone proteins. Together, a picture is emerging in which the impact of Hsp90 inhibitors is shaped by the tumor intracellular and extracellular milieu, and in which Hsp90 inhibitors impact tumor and host on a microenvironmental and systems level. Here we review the tumor intrinsic and extrinsic factors that impact the efficacy of small molecules engaging the Hsp90 chaperone machine.
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HSP90 抑制剂可阻断曲妥珠单抗耐药肿瘤中的 p95-HER2 信号传导并抑制其生长。
影响因子：
8
作者：
Chandarlapaty, S.;Scaltriti, M.;Angelini, P.;Ye, Q.;Guzman, M.;Hudis, C. A.;Norton, L.;Solit, D. B.;Arribas, J.;Baselga, J.;Rosen, N.
通讯作者：
Rosen, N.
影响因子：
4.4
作者：
Bae, Jooeun;Mitsiades, Constantine;Munshi, Nikhil C.
通讯作者：
Munshi, Nikhil C.
影响因子：
11.4
作者：
Donzé, O;Abbas-Terki, T;Picard, D
通讯作者：
Picard, D
DOI：
10.1073/pnas.0903392106
发表时间：
2009-05-19
影响因子：
11.1
作者：
Caldas-Lopes, Eloisi;Cerchietti, Leandro;Chiosis, Gabriela
通讯作者：
Chiosis, Gabriela
影响因子：
21.3
作者：
Connell, P;Ballinger, CA;Patterson, C
通讯作者：
Patterson, C