Heat shock protein 90 (HSP90) is a molecular chaperone of numerous oncoproteins. Therefore, cancer cells can be considered to be 'addicted' to this molecule.
HSP90 is also a mediator of cellular homeostasis. As such, it facilitates numerous transient low-affinity protein–protein interactions that have only recently been identified using bioinformatic and proteomic techniques.
Although primarily a cytoplasmic protein, HSP90 affects diverse nuclear processes, including transcription, chromatin remodelling and DNA damage-induced mutation.
HSP90 is a conformationally dynamic protein. ATP binding to the amino (N) domain and its subsequent hydrolysis by HSP90 drive a conformational cycle that is essential for chaperone activity.
In eukaryotes, co-chaperones and post-translational modifications regulate both client interactions with HSP90 and HSP90 ATPase activity.
Co-chaperones and post-translational modifications can also affect the efficacy of HSP90 inhibitors.
HSP90 inhibitors currently under clinical evaluation interact with the N domain ATP-binding pocket, prevent ATP binding, and stop the chaperone cycle, leading to client protein degradation.
Because of the HSP90 client repertoire, HSP90 inhibitors may combat oncogene switching, which is an important mechanism of tumour escape from tyrosine kinase inhibitors.
Derivatives of the coumarin antibiotic novobiocin represent an alternative strategy for inhibiting HSP90 by targeting a unique carboxy-terminal (C) domain.
Optimal development of HSP90-directed therapeutics will depend on synthesizing information gained from careful genetic analysis of primary and metastatic tumours with an understanding of the unique environmental context in which the tumour is thriving at the expense of the host.
The molecular chaperone heat shock protein 90 (HSP90) has been used by cancer cells to facilitate the function of numerous oncoproteins, and it can be argued that cancer cells are 'addicted' to HSP90. However, although recent reports of the early clinical efficacy of HSP90 inhibitors are encouraging, the optimal use of HSP90-targeted therapeutics will depend on understanding the complexity of HSP90 regulation and the degree to which HSP90 participates in both neoplastic and normal cellular physiology.
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Wandinger, S. K., Richter, K. & Buchner, J. The Hsp90 chaperone machinery. J. Biol. Chem. 283, 18473–18477 (2008).
Zhao, R. et al. Navigating the chaperone network: an integrative map of physical and genetic interactions mediated by the hsp90 chaperone. Cell 120, 715–727 (2005).
Pratt, W. B. & Toft, D. O. Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp. Biol. Med. (Maywood) 228, 111–133 (2003).
Whitesell, L. & Lindquist, S. L. HSP90 and the chaperoning of cancer. Nature Rev. Cancer 5, 761–772 (2005).
Dezwaan, D. C. & Freeman, B. C. HSP90: the Rosetta stone for cellular protein dynamics? Cell Cycle 7, 1006–1012 (2008).
Pratt, W. B., Morishima, Y. & Osawa, Y. The Hsp90 chaperone machinery regulates signaling by modulating ligand binding clefts. J. Biol. Chem. 283, 22885–22889 (2008).
McClellan, A. J. et al. Diverse cellular functions of the Hsp90 molecular chaperone uncovered using systems approaches. Cell 131, 121–135 (2007).
Tsaytler, P. A., Krijgsveld, J., Goerdayal, S. S., Rudiger, S. & Egmond, M. R. Novel Hsp90 partners discovered using complementary proteomic approaches. Cell Stress Chaperones 14, 629–638 (2009).
Freeman, B. C. & Yamamoto, K. R. Disassembly of transcriptional regulatory complexes by molecular chaperones. Science 296, 2232–2235 (2002).
Zhao, R. & Houry, W. A. Hsp90: a chaperone for protein folding and gene regulation. Biochem. Cell Biol. 83, 703–710 (2005).
Tariq, M., Nussbaumer, U., Chen, Y., Beisel, C. & Paro, R. Trithorax requires Hsp90 for maintenance of active chromatin at sites of gene expression. Proc. Natl Acad. Sci. USA 106, 1157–1162 (2009).
Eccles, S. A. et al. NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. Cancer Res. 68, 2850–2860 (2008).
Chiosis, G. & Tao, H. Purine-scaffold Hsp90 inhibitors. IDrugs 9, 778–782 (2006).
Kim, Y. S. et al. Update on Hsp90 inhibitors in clinical trial. Curr. Top. Med. Chem. 9, 1479–1492 (2009).
Workman, P., Burrows, F., Neckers, L. & Rosen, N. Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Ann. N. Y. Acad. Sci. 1113, 202–216 (2007).
Pearl, L. H. & Prodromou, C. Structure and mechanism of the Hsp90 molecular chaperone machinery. Annu. Rev. Biochem. 75, 271–294 (2006).
Donnelly, A. & Blagg, B. S. Novobiocin and additional inhibitors of the Hsp90 C-terminal nucleotide-binding pocket. Curr. Med. Chem. 15, 2702–2717 (2008).
Ali, M. M. et al. Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex. Nature 440, 1013–1017 (2006). This paper describes the first crystal structure of a full-length HSP90–co-chaperone complex.
Prodromou, C. & Pearl, L. H. Structure and functional relationships of Hsp90. Curr. Cancer Drug Targets 3, 301–323 (2003).
Wayne, N. & Bolon, D. N. Dimerization of Hsp90 is required for in vivo function. Design and analysis of monomers and dimers. J. Biol. Chem. 282, 35386–35395 (2007).
Onuoha, S. C., Coulstock, E. T., Grossmann, J. G. & Jackson, S. E. Structural studies on the co-chaperone Hop and its complexes with Hsp90. J. Mol. Biol. 379, 732–744 (2008).
Vaughan, C. K. et al. Structure of an Hsp90-Cdc37-Cdk4 complex. Mol. Cell 23, 697–707 (2006). This paper describes the first structure of an HSP90–co-chaperone–client protein complex.
Southworth, D. R. & Agard, D. A. Species-dependent ensembles of conserved conformational states define the Hsp90 chaperone ATPase cycle. Mol. Cell 32, 631–640 (2008). This paper reports the species-dependence of the conformational states sampled by HSP90.
McLaughlin, S. H., Ventouras, L. A., Lobbezoo, B. & Jackson, S. E. Independent ATPase activity of Hsp90 subunits creates a flexible assembly platform. J. Mol. Biol. 344, 813–826 (2004).
Meyer, P. et al. Structural basis for recruitment of the ATPase activator Aha1 to the Hsp90 chaperone machinery. EMBO J. 23, 1402–1410 (2004).
Mickler, M., Hessling, M., Ratzke, C., Buchner, J. & Hugel, T. The large conformational changes of Hsp90 are only weakly coupled to ATP hydrolysis. Nature Struct. Mol. Biol. 16, 281–286 (2009).
Hessling, M., Richter, K. & Buchner, J. Dissection of the ATP-induced conformational cycle of the molecular chaperone Hsp90. Nature Struct. Mol. Biol. 16, 287–293 (2009). References 26 and 27 dissect the conformational intermediates of the HSP90 chaperone cycle.
Panaretou, B. et al. Activation of the ATPase activity of hsp90 by the stress-regulated cochaperone aha1. Mol. Cell 10, 1307–1318 (2002).
Forafonov, F. et al. p23/Sba1p protects against Hsp90 inhibitors independently of its intrinsic chaperone activity. Mol. Cell. Biol. 28, 3446–3456 (2008).
Retzlaff, M. et al. Asymmetric activation of the hsp90 dimer by its cochaperone aha1. Mol. Cell 37, 344–354 (2010).
Koulov, A. V. et al. Biological and structural basis for Aha1 regulation of Hsp90 ATPase activity in maintaining proteostasis in the human disease cystic fibrosis. Mol. Biol. Cell 21, 871–884 (2010). This paper describes how AHA1 interaction with HSP90 affects client interaction with the HSP90 complex and chaperone efficiency.
Miyata, Y. & Nishida, E. Evaluating CK2 activity with the antibody specific for the CK2-phosphorylated form of a kinase-targeting cochaperone Cdc37. Mol. Cell. Biochem. 316, 127–134 (2008).
Smith, J. R. & Workman, P. Targeting CDC37: an alternative, kinase-directed strategy for disruption of oncogenic chaperoning. Cell Cycle 8, 362–372 (2009).
Echeverria, P. C. et al. Nuclear import of the glucocorticoid receptor-hsp90 complex through the nuclear pore complex is mediated by its interaction with Nup62 and importin β. Mol. Cell. Biol. 29, 4788–4797 (2009).
Pratt, W. B., Morishima, Y., Murphy, M. & Harrell, M. Chaperoning of glucocorticoid receptors. Handb. Exp. Pharmacol. 172, 111–138 (2006).
Wochnik, G. M. et al. FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells. J. Biol. Chem. 280, 4609–4616 (2005).
Zhang, M. et al. Structural and functional coupling of Hsp90- and Sgt1-centred multi-protein complexes. EMBO J. 27, 2789–2798 (2008).
Boulon, S. et al. The Hsp90 chaperone controls the biogenesis of L7Ae RNPs through conserved machinery. J. Cell Biol. 180, 579–595 (2008).
Vaughan, C. K. et al. Hsp90-dependent activation of protein kinases is regulated by chaperone-targeted dephosphorylation of Cdc37. Mol. Cell 31, 886–895 (2008).
McDowell, C. L., Bryan Sutton, R. & Obermann, W. M. Expression of Hsp90 chaperone [corrected] proteins in human tumor tissue. Int. J. Biol. Macromol. 45, 310–314 (2009).
Gray, P. J. Jr, Stevenson, M. A. & Calderwood, S. K. Targeting Cdc37 inhibits multiple signaling pathways and induces growth arrest in prostate cancer cells. Cancer Res. 67, 11942–11950 (2007).
Holmes, J. L., Sharp, S. Y., Hobbs, S. & Workman, P. Silencing of HSP90 cochaperone AHA1 expression decreases client protein activation and increases cellular sensitivity to the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin. Cancer Res. 68, 1188–1197 (2008).
Scroggins, B. T. & Neckers, L. Post-translational modification of heat shock protein 90: impact on chaperone function. Expert Opin. Drug Discov. 2, 1403–1414 (2007).
Mimnaugh, E. G., Worland, P. J., Whitesell, L. & Neckers, L. M. Possible role for serine/threonine phosphorylation in the regulation of the heteroprotein complex between the hsp90 stress protein and the pp60v-src tyrosine kinase. J. Biol. Chem. 270, 28654–28659 (1995).
Wandinger, S. K., Suhre, M. H., Wegele, H. & Buchner, J. The phosphatase Ppt1 is a dedicated regulator of the molecular chaperone Hsp90. EMBO J. 25, 367–376 (2006).
Duval, M., Le Boeuf, F., Huot, J. & Gratton, J. P. Src-mediated phosphorylation of Hsp90 in response to vascular endothelial growth factor (VEGF) is required for VEGF receptor-2 signaling to endothelial NO synthase. Mol. Biol. Cell 18, 4659–4668 (2007). This paper reports the tyrosine phosphorylation of HSP90 by a client kinase.
Kurokawa, M., Zhao, C., Reya, T. & Kornbluth, S. Inhibition of apoptosome formation by suppression of Hsp90β phosphorylation in tyrosine kinase-induced leukemias. Mol. Cell. Biol. 28, 5494–5506 (2008).
Old, W. M. et al. Functional proteomics identifies targets of phosphorylation by B-Raf signaling in melanoma. Mol. Cell 34, 115–131 (2009).
Lees-Miller, S. P. & Anderson, C. W. Two human 90-kDa heat shock proteins are phosphorylated in vivo at conserved serines that are phosphorylated in vitro by casein kinase II. J. Biol. Chem. 264, 2431–2437 (1989).
Miyata, Y. Protein kinase CK2 in health and disease: CK2: the kinase controlling the Hsp90 chaperone machinery. Cell. Mol. Life Sci. 66, 1840–1849 (2009).
Harvey, S. L., Charlet, A., Haas, W., Gygi, S. P. & Kellogg, D. R. Cdk1-dependent regulation of the mitotic inhibitor Wee1. Cell 122, 407–420 (2005).
Mollapour, M. et al. Swe1Wee1-dependent tyrosine phosphorylation of Hsp90 regulates distinct facets of chaperone function. Mol. Cell 37, 333–343 (2010).
Mollapour, M., Tsutsumi, S. & Neckers, L. Hsp90 phosphorylation, Wee1 and the cell cycle. Cell Cycle 9, 1–7 (2010).
Yu, X. et al. Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228. J. Natl Cancer Inst. 94, 504–513 (2002).
Kovacs, J. J. et al. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol. Cell 18, 601–607 (2005).
Scroggins, B. T. et al. An acetylation site in the middle domain of Hsp90 regulates chaperone function. Mol. Cell 25, 151–159 (2007).
Yang, Y. et al. Role of acetylation and extracellular location of heat shock protein 90α in tumor cell invasion. Cancer Res. 68, 4833–4842 (2008).
Maloney, A. et al. Gene and protein expression profiling of human ovarian cancer cells treated with the heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin. Cancer Res. 67, 3239–3253 (2007).
Martinez-Ruiz, A. et al. S-nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities. Proc. Natl Acad. Sci. USA 102, 8525–8530 (2005).
Morra, G., Verkhivker, G. & Colombo, G. Modeling signal propagation mechanisms and ligand-based conformational dynamics of the Hsp90 molecular chaperone full-length dimer. PLoS Comput. Biol. 5, e1000323 (2009).
Retzlaff, M. et al. Hsp90 is regulated by a switch point in the C-terminal domain. EMBO Rep. 10, 1147–1153 (2009).
Compton, S. A., Elmore, L. W., Haydu, K., Jackson-Cook, C. K. & Holt, S. E. Induction of nitric oxide synthase-dependent telomere shortening after functional inhibition of Hsp90 in human tumor cells. Mol. Cell. Biol. 26, 1452–1462 (2006).
Toogun, O. A., Dezwaan, D. C. & Freeman, B. C. The hsp90 molecular chaperone modulates multiple telomerase activities. Mol. Cell. Biol. 28, 457–467 (2008).
Csermely, P., Schnaider, T., Soti, C., Prohaszka, Z. & Nardai, G. The 90-kDa molecular chaperone family: structure, function, and clinical applications. A comprehensive review. Pharmacol. Ther. 79, 129–168 (1998).
Conzen, S. D. Minireview: nuclear receptors and breast cancer. Mol. Endocrinol. 22, 2215–2228 (2008).
Echeverria, P. C. & Picard, D. Molecular chaperones, essential partners of steroid hormone receptors for activity and mobility. Biochim. Biophys. Acta 1803, 641–649 (2009).
Zou, J., Guo, Y., Guettouche, T., Smith, D. F. & Voellmy, R. Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Cell 94, 471–480 (1998).
Conde, R., Belak, Z. R., Nair, M., O'Carroll, R. F. & Ovsenek, N. Modulation of Hsf1 activity by novobiocin and geldanamycin. Biochem. Cell Biol. 87, 845–851 (2009).
Dai, C., Whitesell, L., Rogers, A. B. & Lindquist, S. Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 130, 1005–1018 (2007).
Min, J. N., Huang, L., Zimonjic, D. B., Moskophidis, D. & Mivechi, N. F. Selective suppression of lymphomas by functional loss of Hsf1 in a p53-deficient mouse model for spontaneous tumors. Oncogene 26, 5086–5097 (2007). References 69 and 70 highlight the importance of HSF1 for carcinogenesis.
Au, Q., Zhang, Y., Barber, J. R., Ng, S. C. & Zhang, B. Identification of inhibitors of HSF1 functional activity by high-content target-based screening. J. Biomol. Screen. 14, 1165–1175 (2009).
Ci, W. et al. The BCL6 transcriptional program features repression of multiple oncogenes in primary B cells and is deregulated in DLBCL. Blood 113, 5536–5548 (2009).
Cerchietti, L. C. et al. A peptomimetic inhibitor of BCL6 with potent antilymphoma effects in vitro and in vivo. Blood 113, 3397–3405 (2009).
Cerchietti, L. C. et al. A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas. Nature Med. 15, 1369–1376 (2009).
Choo, A. et al. The role of IRF1 and IRF2 transcription factors in leukaemogenesis. Curr. Gene Ther. 6, 543–550 (2006).
Narayan, V., Eckert, M., Zylicz, A., Zylicz, M. & Ball, K. L. Cooperative regulation of the interferon regulatory factor-1 tumor suppressor protein by core components of the molecular chaperone machinery. J. Biol. Chem. 284, 25889–25899 (2009).
Bach, C. & Slany, R. K. Molecular pathology of mixed-lineage leukemia. Future Oncol. 5, 1271–1281 (2009).
Pal, S., Vishwanath, S. N., Erdjument-Bromage, H., Tempst, P. & Sif, S. Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes. Mol. Cell. Biol. 24, 9630–9645 (2004).
Hamamoto, R. et al. SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nature Cell Biol. 6, 731–740 (2004). This paper reports that HSP90 inhibitor treatment suppresses SMYD3 activity in cancer cells.
Komatsu, S. et al. Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous cell carcinoma. Carcinogenesis 30, 1139–1146 (2009).
Abu-Farha, M. et al. The tale of two domains: proteomics and genomics analysis of SMYD2, a new histone methyltransferase. Mol. Cell. Proteomics 7, 560–572 (2008).
Sekimoto, T. et al. The molecular chaperone Hsp90 regulates accumulation of DNA polymerase η at replication stalling sites in UV-irradiated cells. Mol. Cell 37, 79–89 (2010).
Specchia, V. et al. Hsp90 prevents phenotypic variation by suppressing the mutagenic activity of transposons. Nature 463, 662–665 (2010).
Brennecke, J. et al. Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila. Cell 128, 1089–1103 (2007).
Nishida, K. M. et al. Functional involvement of Tudor and dPRMT5 in the piRNA processing pathway in Drosophila germlines. EMBO J. 28, 3820–3831 (2009).
Oh, W. K. et al. A single arm phase II trial of IPI-504 in patients with castration resistant prostate cancer (CRPC). Genitourinary Cancers Symp. Abstr. 219 (2009).
Heath, E. I. et al. A phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with hormone-refractory metastatic prostate cancer. Clin. Cancer Res. 14, 7940–7946 (2008).
Yano, A. et al. Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone. Proc. Natl Acad. Sci. USA 105, 15541–15546 (2008).
Zoubeidi, A. et al. Cooperative interactions between androgen receptor (AR) and heat-shock protein 27 facilitate AR transcriptional activity. Cancer Res. 67, 10455–10465 (2007).
Solit, D. B. et al. Phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with metastatic melanoma. Clin. Cancer Res. 14, 8302–8307 (2008).
Grbovic, O. M. et al. V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors. Proc. Natl Acad. Sci. USA 103, 657–662 (2006).
da Rocha Dias, S. et al. Activated B-RAF is an Hsp90 client protein that is targeted by the anticancer drug 17-allylamino-17-demethoxygeldanamycin. Cancer Res. 65, 10686–10691 (2005).
Mimnaugh, E. G., Chavany, C. & Neckers, L. Polyubiquitination and proteasomal degradation of the p185c-erbB-2 receptor protein-tyrosine kinase induced by geldanamycin. J. Biol. Chem. 271, 22796–22801 (1996).
Modi, S. et al. Phase II trial of the Hsp90 inhibitor tanespimycin (Tan) + trastuzumab (T) in patients (pts) with HER2-positive metastatic breast cancer (MBC). J. Clin. Oncol. Abstr. 26, 1027 (2008).
Xu, W. et al. Sensitivity of epidermal growth factor receptor and ErbB2 exon 20 insertion mutants to Hsp90 inhibition. Br. J. Cancer 97, 741–744 (2007).
Chandarlapaty, S. et al. Inhibitors of HSP90 block p95-HER2 signaling in Trastuzumab-resistant tumors and suppress their growth. Oncogene 29, 325–334 (2009).
Caldas-Lopes, E. et al. Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. Proc. Natl Acad. Sci. USA 106, 8368–8373 (2009).
Richardson, P. G. et al. Tanespimycin + bortezomib demonstrates safety, activity, and effective target inhibition in relapsed/refractory myeloma patients: updated results of a phase 1/2 study. 51st Am. Soc. Hematogy Annu. Meet. Abstr. (2009).
Mimnaugh, E. G., Xu, W., Vos, M., Yuan, X. & Neckers, L. Endoplasmic reticulum vacuolization and valosin-containing protein relocalization result from simultaneous hsp90 inhibition by geldanamycin and proteasome inhibition by velcade. Mol. Cancer Res. 4, 667–681 (2006).
Mitsiades, C. S. et al. Antimyeloma activity of heat shock protein-90 inhibition. Blood 107, 1092–1100 (2006).
Frebel, K. & Wiese, S. Signalling molecules essential for neuronal survival and differentiation. Biochem. Soc. Trans. 34, 1287–1290 (2006).
Fionda, C. et al. Heat shock protein-90 inhibitors increase MHC class I-related chain A and B ligand expression on multiple myeloma cells and their ability to trigger NK cell degranulation. J. Immunol. 183, 4385–4394 (2009). This paper shows that HSP90 inhibitors enhance NK-dependent recognition and lysis of myleoma cells in an HSF1-dependent manner.
Tse, A. N., Sheikh, T. N., Alan, H., Chou, T. C. & Schwartz, G. K. 90-kDa heat shock protein inhibition abrogates the topoisomerase I poison-induced G2/M checkpoint in p53-null tumor cells by depleting Chk1 and Wee1. Mol. Pharmacol. 75, 124–133 (2009).
Arlander, S. J. et al. Chaperoning checkpoint kinase 1 (Chk1), an Hsp90 client, with purified chaperones. J. Biol. Chem. 281, 2989–2998 (2006).
Tse, A. N. et al. A phase 1 dose-escalation study of irinotecan in combination with 17-allylamino-17-demethoxygeldanamycin in patients with solid tumors. Clin. Cancer Res. 14, 6704–6711 (2008).
Hubbard, J. et al. Phase I study of 17-allylamino-17 demethoxygeldanamycin, gemcitabine and/or cisplatin in patients with refractory solid tumors. Invest. New Drugs 15 Jan 2010 [epub ahead of print].
Hwang, M., Moretti, L. & Lu, B. HSP90 inhibitors: multi-targeted antitumor effects and novel combinatorial therapeutic approaches in cancer therapy. Curr. Med. Chem. 16, 3081–3092 (2009).
Reikvam, H., Ersvaer, E. & Bruserud, O. Heat shock protein 90 - a potential target in the treatment of human acute myelogenous leukemia. Curr. Cancer Drug Targets 9, 761–776 (2009).
Lancet, J. E. et al. Phase I study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022,17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia. Leukemia 24, 699–705 (2010).
Weisberg, E. et al. FLT3 inhibition and mechanisms of drug resistance in mutant FLT3-positive AML. Drug Resist. Updat. 12, 81–89 (2009).
Shiotsu, Y. et al. Novel oxime derivatives of radicicol induce erythroid differentiation associated with preferential G1 phase accumulation against chronic myelogenous leukemia cells through destabilization of Bcr-Abl with Hsp90 complex. Blood 96, 2284–2291 (2000).
Peng, C., Li, D. & Li, S. Heat shock protein 90: a potential therapeutic target in leukemic progenitor and stem cells harboring mutant BCR-ABL resistant to kinase inhibitors. Cell Cycle 6, 2227–2231 (2007).
O'Hare, T., Eide, C. A. & Deininger, M. W. New Bcr-Abl inhibitors in chronic myeloid leukemia: keeping resistance in check. Expert Opin. Investig. Drugs 17, 865–878 (2008).
Peng, C. et al. Inhibition of heat shock protein 90 prolongs survival of mice with BCR-ABL-T315I-induced leukemia and suppresses leukemic stem cells. Blood 110, 678–685 (2007).
Castro, J. E. et al. ZAP-70 is a novel conditional heat shock protein 90 (Hsp90) client: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling in chronic lymphocytic leukemia. Blood 106, 2506–2512 (2005).
Elfiky, A. et al. BIIB021, an oral, synthetic non-ansamycin Hsp90 inhibitor: phase I experience. J. Clin. Oncol. Abstr. 26, 2503 (2008).
Gallegos Ruiz, M. I. et al. Integration of gene dosage and gene expression in non-small cell lung cancer, identification of HSP90 as potential target. PLoS ONE 3, e0001722 (2008).
Sequist, L. V. et al. A phase II trial of IPI-504 (retaspimycin hydrochloride), a novel Hsp90 inhibitor, in patients with relapsed and/or refractory stage IIIb or stage IV non-small cell lung cancer (NSCLC) stratified by EGFR mutation status. J. Clin. Oncol. Abstr. 27, 8073 (2009).
Shimamura, T. & Shapiro, G. I. Heat shock protein 90 inhibition in lung cancer. J. Thorac. Oncol. 3, S152–S159 (2008).
Shimamura, T. et al. Hsp90 inhibition suppresses mutant EGFR-T790M signaling and overcomes kinase inhibitor resistance. Cancer Res. 68, 5827–5838 (2008).
Banerji, U. et al. Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J. Clin. Oncol. 23, 4152–4161 (2005).
Grem, J. L. et al. Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors. J. Clin. Oncol. 23, 1885–1893 (2005).
Ramanathan, R. K. et al. Phase I pharmacokinetic and pharmacodynamic study of 17-dimethylaminoethylamino-17-demethoxygeldanamycin, an inhibitor of heat-shock protein 90, in patients with advanced solid tumors. J. Clin. Oncol. 28, 1520–1526 (2010).
Eiseman, J. L. et al. Pharmacokinetics and pharmacodynamics of 17-demethoxy 17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) in C.B-17 SCID mice bearing MDA-MB-231 human breast cancer xenografts. Cancer Chemother. Pharmacol. 55, 21–32 (2005).
Vilenchik, M. et al. Targeting wide-range oncogenic transformation via PU24FCl, a specific inhibitor of tumor Hsp90. Chem. Biol. 11, 787–797 (2004).
Kamal, A. et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425, 407–410 (2003).
Kummar, S. et al. Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies. Eur. J. Cancer 46, 340–347 (2010).
Dakappagari, N. et al. An investigation into the potential use of serum Hsp70 as a novel tumour biomarker for Hsp90 inhibitors. Biomarkers 15, 31–38 (2009).
Demetri, G. D. et al. Inhibition of the heat shock protein 90 (Hsp90) chaperone with the novel agent IPI-504 to overcome resistance to tyrosine kinase inhibitors (TKIs) in metastatic GIST: updated results of a phase I trial. J. Clin. Oncol. Abstr. 25, 10024 (2007).
Smith-Jones, P. M., Solit, D., Afroze, F., Rosen, N. & Larson, S. M. Early tumor response to Hsp90 therapy using HER2 PET: comparison with 18F-FDG PET. J. Nucl. Med. 47, 793–796 (2006). This paper describes a new non-invasive imaging approach to monitor anti-tumour HSP90 inhibitor activity in vivo.
Oude Munnink, T. H. et al. 89Zr-trastuzumab PET visualises HER2 downregulation by the HSP90 inhibitor NVP-AUY922 in a human tumour xenograft. Eur. J. Cancer 46, 678–684 (2009).
Kramer-Marek, G., Kiesewetter, D. O. & Capala, J. Changes in HER2 expression in breast cancer xenografts after therapy can be quantified using PET and 18F-labeled affibody molecules. J. Nucl. Med. 50, 1131–1139 (2009).
Holland, J. P. et al. Measuring the pharmacodynamic effects of a novel Hsp90 inhibitor on HER2/neu expression in mice using Zr-DFO-trastuzumab. PLoS ONE 5, e8859 (2010).
Le, H. C. et al. Proton MRS detects metabolic changes in hormone sensitive and resistant human prostate cancer models CWR22 and CWR22r. Magn. Reson. Med. 62, 1112–1119 (2009).
Chung, Y. L. et al. Magnetic resonance spectroscopic pharmacodynamic markers of the heat shock protein 90 inhibitor 17-allylamino, 17-demethoxygeldanamycin (17AAG) in human colon cancer models. J. Natl Cancer Inst. 95, 1624–1633 (2003).
Liu, D. et al. Use of radiolabelled choline as a pharmacodynamic marker for the signal transduction inhibitor geldanamycin. Br. J. Cancer 87, 783–789 (2002).
Kelland, L. R., Sharp, S. Y., Rogers, P. M., Myers, T. G. & Workman, P. DT-Diaphorase expression and tumor cell sensitivity to 17-allylamino, 17-demethoxygeldanamycin, an inhibitor of heat shock protein 90. J. Natl Cancer Inst. 91, 1940–1949 (1999).
Guo, W. et al. Formation of 17-allylamino-demethoxygeldanamycin (17-AAG) hydroquinone by NAD(P)H:quinone oxidoreductase 1: role of 17-AAG hydroquinone in heat shock protein 90 inhibition. Cancer Res. 65, 10006–10015 (2005).
Gaspar, N. et al. Acquired resistance to 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) in glioblastoma cells. Cancer Res. 69, 1966–1975 (2009).
Erlichman, C. Tanespimycin: the opportunities and challenges of targeting heat shock protein 90. Expert Opin. Investig. Drugs 18, 861–868 (2009).
McCollum, A. K., Teneyck, C. J., Sauer, B. M., Toft, D. O. & Erlichman, C. Up-regulation of heat shock protein 27 induces resistance to 17-allylamino-demethoxygeldanamycin through a glutathione-mediated mechanism. Cancer Res. 66, 10967–10975 (2006).
Powers, M. V., Clarke, P. A. & Workman, P. Dual targeting of HSC70 and HSP72 inhibits HSP90 function and induces tumor-specific apoptosis. Cancer Cell 14, 250–262 (2008).
Evans, C. G., Chang, L. & Gestwicki, J. E. Heat shock protein 70 (Hsp70) as an emerging drug target. J. Med. Chem. 24 Mar 2010 (doi:10.1021/jm100054f).
Powers, M. V. et al. Targeting HSP70: the second potentially druggable heat shock protein and molecular chaperone? Cell Cycle 9, 1542–1550 (2010).
Hadchity, E. et al. Heat shock protein 27 as a new therapeutic target for radiation sensitization of head and neck squamous cell carcinoma. Mol. Ther. 17, 1387–1394 (2009).
Roe, S. M. et al. Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin. J. Med. Chem. 42, 260–266 (1999).
Prodromou, C. et al. Structural basis of the radicicol resistance displayed by a fungal hsp90. ACS Chem. Biol. 4, 289–297 (2009).
Matthews, S. B. et al. Characterization of a novel novobiocin analogue as a putative C-terminal inhibitor of heat shock protein 90 in prostate cancer cells. Prostate 70, 27–36 (2010).
Shelton, S. N. et al. KU135, a novel novobiocin-derived C-terminal inhibitor of the 90-kDa heat shock protein, exerts potent antiproliferative effects in human leukemic cells. Mol. Pharmacol. 76, 1314–1322 (2009). References 148 and 149 describe new C-terminal HSP90 inhibitors with potent anticancer activity.
Radanyi, C. et al. Antiproliferative and apoptotic activities of tosylcyclonovobiocic acids as potent heat shock protein 90 inhibitors in human cancer cells. Cancer Lett. 274, 88–94 (2009).
Zhang, T. et al. A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells. Mol. Cancer Ther. 7, 162–170 (2008).
Sreeramulu, S., Gande, S. L., Gobel, M. & Schwalbe, H. Molecular mechanism of inhibition of the human protein complex Hsp90-Cdc37, a kinome chaperone-cochaperone, by triterpene celastrol. Angew. Chem. Int. Ed. Engl. 48, 5853–5855 (2009).
Chakraborty, A. et al. HSP90 regulates cell survival via inositol hexakisphosphate kinase-2. Proc. Natl Acad. Sci. USA 105, 1134–1139 (2008).
Voss, A. K., Thomas, T. & Gruss, P. Mice lacking HSP90β fail to develop a placental labyrinth. Development 127, 1–11 (2000).
Dollins, D. E., Warren, J. J., Immormino, R. M. & Gewirth, D. T. Structures of GRP94-nucleotide complexes reveal mechanistic differences between the hsp90 chaperones. Mol. Cell 28, 41–56 (2007).
Frey, S., Leskovar, A., Reinstein, J. & Buchner, J. The ATPase cycle of the endoplasmic chaperone Grp94. J. Biol. Chem. 282, 35612–35620 (2007).
Leskovar, A., Wegele, H., Werbeck, N. D., Buchner, J. & Reinstein, J. The ATPase cycle of the mitochondrial Hsp90 analog Trap1. J. Biol. Chem. 283, 11677–11688 (2008).
Immormino, R. M. et al. Different poses for ligand and chaperone in inhibitor-bound Hsp90 and GRP94: implications for paralog-specific drug design. J. Mol. Biol. 388, 1033–1042 (2009).
Felts, S. J. et al. The hsp90-related protein TRAP1 is a mitochondrial protein with distinct functional properties. J. Biol. Chem. 275, 3305–3312 (2000).
Hua, G., Zhang, Q. & Fan, Z. Heat shock protein 75 (TRAP1) antagonizes reactive oxygen species generation and protects cells from granzyme M-mediated apoptosis. J. Biol. Chem. 282, 20553–20560 (2007).
Kang, B. H. et al. Combinatorial drug design targeting multiple cancer signaling networks controlled by mitochondrial Hsp90. J. Clin. Invest. 119, 454–464 (2009).
Leav, I. et al. Cytoprotective mitochondrial chaperone TRAP-1 as a novel molecular target in localized and metastatic prostate cancer. Am. J. Pathol. 176, 393–401 (2009).
Pridgeon, J. W., Olzmann, J. A., Chin, L. S. & Li, L. PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol. 5, e172 (2007).
Sidera, K. & Patsavoudi, E. Extracellular HSP90: conquering the cell surface. Cell Cycle 7, 1564–1568 (2008).
Eustace, B. K. et al. Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness. Nature Cell Biol. 6, 507–514 (2004). This paper describes an important role for secreted HSP90 in cancer cell motility and invasion.
Becker, B. et al. Induction of Hsp90 protein expression in malignant melanomas and melanoma metastases. Exp. Dermatol. 13, 27–32 (2004).
Tsutsumi, S. et al. A small molecule cell-impermeant Hsp90 antagonist inhibits tumor cell motility and invasion. Oncogene 27, 2478–2487 (2008).
Cheng, C. F. et al. Transforming growth factor alpha (TGFα)-stimulated secretion of HSP90alpha: using the receptor LRP-1/CD91 to promote human skin cell migration against a TGFβ-rich environment during wound healing. Mol. Cell. Biol. 28, 3344–3358 (2008).
Li, W. et al. Extracellular heat shock protein-90α: linking hypoxia to skin cell motility and wound healing. EMBO J. 26, 1221–1233 (2007).
Tsutsumi, S. et al. Hsp90 charged-linker truncation reverses the functional consequences of weakened hydrophobic contacts in the N domain. Nature Struct. Mol. Biol. 16, 1141–1147 (2009).
Sidera, K., Gaitanou, M., Stellas, D., Matsas, R. & Patsavoudi, E. A critical role for HSP90 in cancer cell invasion involves interaction with the extracellular domain of HER-2. J. Biol. Chem. 283, 2031–2041 (2008).
Annamalai, B., Liu, X., Gopal, U. & Isaacs, J. S. Hsp90 is an essential regulator of EphA2 receptor stability and signaling: implications for cancer cell migration and metastasis. Mol. Cancer Res. 7, 1021–1032 (2009).
Kawabe, M. et al. Heat shock protein 90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin enhances EphA2+ tumor cell recognition by specific CD8+ T cells. Cancer Res. 69, 6995–7003 (2009).
Wesa, A. K. et al. Enhancement in specific CD8+ T cell recognition of EphA2+ tumors in vitro and in vivo after treatment with ligand agonists. J. Immunol. 181, 7721–7727 (2008).
Stuehler, C. et al. Selective depletion of alloreactive T cells by targeted therapy of heat shock protein 90: a novel strategy for control of graft-versus-host disease. Blood 114, 2829–2836 (2009).
The authors would like to thank K. Beebe, Y. S. Kim, and all members of the Neckers and Trepel laboratories for their helpful comments.
The authors declare no competing financial interests.
National Cancer Institute Drug Dictionary
Protein that assists or alters the function of other chaperones.
- Oncogene addiction
The hypothesis that tumours arising as a result of a particular oncogenic lesion are dependent on the continued expression of that oncogene.
Specialized assembly of proteins that binds to a region of the chromosome called the centromere and is essential for chromosome segregation during eukaryotic cell division.
A caspase-activating complex that is formed when cytochrome c is released from mitochondria. It initiates oligomerization of APAF1, which binds procaspase-9 and thereby initiates the caspase cascade that leads to programmed cell death.
The covalent attachment of a nitrogen monoxide group to the thiol side chain of cysteine.
- Proteotoxic stress
Protein damage caused by physical or chemical agents such as heat, heavy metals, hypoxia and some anticancer drugs.
- DNA polymerase-η
A member of the DNA polymerase Y family, a group of low-fidelity DNA polymerases that can replicate through damaged DNA.
Mobile genetic element that can insert in different positions in the genome and cause mutations.
- Piwi-interacting RNA (piRNA)
A class of germline-specific small RNA molecule that suppresses transposon mobility by RNA silencing.
- Castrate-resistant prostate cancer
Prostate cancer that no longer responds to androgen deprivation therapy.
- Prostate-specific antigen (PSA)
A protein produced by the prostate that is increased in the blood of men with prostate cancer, benign prostatic hyperplasia, or infection and inflammation of the prostate.
The relationship between drug concentration (pharmacokinetics) and its biological effects (what the drug does to the body).
A humanized monoclonal antibody that binds HER2 on tumour cells and prevents uncontrolled proliferation caused by aberrant HER2 signalling.
A set of published rules that define when cancer patients improve ('respond'), stay the same ('stable') or worsen ('progression') during treatments.
- Triple-negative breast cancer
Breast cancer that lacks expression of oestrogen, progesterone and HER2 receptors.
Refers to any disease or injury affecting nerves or nerve cells.
- Graft-versus-host disease
A common complication of allogeneic bone marrow transplantation in which functional immune cells in the transplanted marrow recognize the recipient as foreign and mount an immunological attack.
- Alloreactive T cell
White blood cell that recognizes a complex composed of a major histocompatibility complex (MHC) molecule and a peptide in which the MHC or peptide are derived from a genetically different member of the same species.
A radio-labelled imaging methodology for detecting cancers that relies on increased glucose uptake by the tumour — a characteristic of cancers and other pathologies.
- Proton magnetic resonance
The resonance of protons to radiation in a magnetic field. Proton magnetic resonance spectra yield a great deal of information about molecular structure as most organic molecules contain hydrogen atoms that absorb energy of different wavelengths depending on their bonding environment.
- Non-ansamycin HSP90 inhibitor
HSP90 inhibitor lacking the benzoquinone ansamycin backbone found in tanespimycin (17-AAG), alvespimycin (17-DMAG) and retaspimycin (IPI-504).
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Trepel, J., Mollapour, M., Giaccone, G. et al. Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 10, 537–549 (2010). https://doi.org/10.1038/nrc2887
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