HSP90分子伴侶循環(huán),，圖片來自維基共享資源,。
根據2012年1月23日在線發(fā)表在Journal of Experimental Medicine期刊上的兩篇論文，靶向單個蛋白能夠有助于對抗乳腺癌和白血病(leukemia, 譯者注：也常譯作血癌),。
這種單個蛋白是HSP90,，它在細胞中作為分子伴侶保護其他蛋白。
德國哥廷根大學(University of Göttingen) Ute Moll領導的一個研究小組發(fā)現阻斷HSP90活性使得正常情況下得到保護的蛋白容易遭受攻擊和破壞,。這些蛋白之一就是移動抑制因子(migration inhibitory factor, MIF),，它促進乳腺腫瘤生長。在小鼠中,，HSP90抑制物延緩表達MIF的乳腺腫瘤的生長,，但是對缺乏MIF的腫瘤沒有影響。
根據美國達納法伯癌癥研究所(Dana-Farber Cancer Institute) David Weinstock和同事們開展的一項研究,， HSP90抑制物對治療某些白血病形式也是大有希望的,。他們證實HSP90抑制物延緩由于過度活性的酶JAK2版本促進的血癌生長，其中很多過度活性的JAK2版本抵抗阻斷JAK2的藥物,。在小鼠中,，HSP90抑制物延遲抗性白血病細胞生長。
這兩項研究綜合在一起意味著在很多癌癥中HSP90可能代表著一種治療性靶標,。(生物谷：towersimper編譯)
doi:10.1084/jem.20111117
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Inhibiting the HSP90 chaperone destabilizes macrophage migration inhibitory factor and thereby inhibits breast tumor progression
Ramona Schulz, Natalia D. Marchenko, Lena Holembowski, Günter Fingerle-Rowson, Marina Pesic, Lars Zender, Matthias Dobbelstein, and Ute M. Moll
Intracellular macrophage migration inhibitory factor (MIF) often becomes stabilized in human cancer cells. MIF can promote tumor cell survival, and elevated MIF protein correlates with tumor aggressiveness and poor prognosis. However, the molecular mechanism facilitating MIF stabilization in tumors is not understood. We show that the tumor-activated HSP90 chaperone complex protects MIF from degradation. Pharmacological inhibition of HSP90 activity, or siRNA-mediated knockdown of HSP90 or HDAC6, destabilizes MIF in a variety of human cancer cells. The HSP90-associated E3 ubiquitin ligase CHIP mediates the ensuing proteasome-dependent MIF degradation. Cancer cells contain constitutive endogenous MIF–HSP90 complexes. siRNA-mediated MIF knockdown inhibits proliferation and triggers apoptosis of cultured human cancer cells, whereas HSP90 inhibitor-induced apoptosis is overridden by ectopic MIF expression. In the ErbB2 transgenic model of human HER2-positive breast cancer, genetic ablation of MIF delays tumor progression and prolongs overall survival of mice. Systemic treatment with the HSP90 inhibitor 17AAG reduces MIF expression and blocks growth of MIF-expressing, but not MIF-deficient, tumors. Together, these findings identify MIF as a novel HSP90 client and suggest that HSP90 inhibitors inhibit ErbB2-driven breast tumor growth at least in part by destabilizing MIF.
doi:10.1084/jem.20111694
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Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition
Oliver Weigert, Andrew A. Lane, Liat Bird, Nadja Kopp, Bjoern Chapuy, Diederik van Bodegom, Angela V. Toms, Sachie Marubayashi, et al.
Enzymatic inhibitors of Janus kinase 2 (JAK2) are in clinical development for the treatment of myeloproliferative neoplasms (MPNs), B cell acute lymphoblastic leukemia (B-ALL) with rearrangements of the cytokine receptor subunit cytokine receptor–like factor 2 (CRLF2), and other tumors with constitutive JAK2 signaling. In this study, we identify G935R, Y931C, and E864K mutations within the JAK2 kinase domain that confer resistance across a panel of JAK inhibitors, whether present in cis with JAK2 V617F (observed in MPNs) or JAK2 R683G (observed in B-ALL). G935R, Y931C, and E864K do not reduce the sensitivity of JAK2-dependent cells to inhibitors of heat shock protein 90 (HSP90), which promote the degradation of both wild-type and mutant JAK2. HSP90 inhibitors were 100–1,000-fold more potent against CRLF2-rearranged B-ALL cells, which correlated with JAK2 degradation and more extensive blockade of JAK2/STAT5, MAP kinase, and AKT signaling. In addition, the HSP90 inhibitor AUY922 prolonged survival of mice xenografted with primary human CRLF2-rearranged B-ALL further than an enzymatic JAK2 inhibitor. Thus, HSP90 is a promising therapeutic target in JAK2-driven cancers, including those with genetic resistance to JAK enzymatic inhibitors.
