Role of HSP90 Inhibitors in the Treatment of Cancer

  • Geraldine O’Sullivan Coyne
  • Cecilia Monge
  • Alice P. ChenEmail author
Part of the Heat Shock Proteins book series (HESP, volume 19)


The 90-kDa heat shock protein HSP90 is a member of a highly evolutionarily conserved class of molecular chaperone proteins indispensable for the development of cancer; when activated by cellular stress, HSP90 stabilizes oncogenic substrate “client” proteins involved in cellular processes that promote tumorigenesis. HSP90 inhibition attenuates this stabilization of aberrant client proteins in tumor cells, allowing for simultaneous targeting of multiple pathways involved in cancer cell survival. HSP90 inhibitors have been assessed as potential oncologic therapies in several preclinical and clinical studies. Although preclinically promising results have been measured, these results have not translated yet into major clinical efficacy. Combinations of HSP90 inhibitors with approved and investigational oncology drugs may represent further opportunities for the use of these agents in patients with cancer. This chapter reviews some of the important early clinical milestones observed in studies of first- and second-generation HSP90 inhibitors used as single agents and in combination. In the conclusion, possible reasons for the lack of therapeutic benefit in clinical studies are considered.


Angiogenesis Heat shock protein 90 HSP90 inhibitor Metastasis Molecular chaperone Oncogenic driver 



Adverse event


Anaplastic lymphoma kinase


Serine/threonine-protein kinases B-Raf


Cyclin-dependent kinase


Serine/threonine-protein kinases C-Raf


Colorectal carcinoma


Dose-limiting toxicity


Epidermal growth factor receptor


Epithelial-to-mesenchymal transition


Glial cell line-derived neurotrophic factor


Human epidermal growth factor receptor 2


Hepatocyte growth factor


Heat shock protein


Heat shock protein 90


Metastatic breast cancer


Maximum tolerated dose


Non-small cell lung cancer


Overall response rate


Triple-negative breast cancer



Special thanks to Sarah Miller, PhD.


  1. Acquaviva J, Smith DL, Jimenez J-P, Zhang C, Sequeira M, He S et al (2014) Overcoming acquired BRAF inhibitor resistance in melanoma via targeted inhibition of Hsp90 with Ganetespib. Mol Cancer Ther 13:353–363PubMedCrossRefPubMedCentralGoogle Scholar
  2. Ahsan A, Ramanand SG, Whitehead C, Hiniker SM, Rehemtulla A, Pratt WB et al (2012) Wild-type EGFR is stabilized by direct interaction with HSP90 in cancer cells and tumors. Neoplasia 14:670–677PubMedPubMedCentralCrossRefGoogle Scholar
  3. Akce M, Alese OB, Shaib WL, Wu CS-Y, Lesinski GB, El-Rayes BF (2018) Phase Ib trial of pembrolizumab and XL888 in patients with advanced gastrointestinal malignancies. J Clin Oncol 36:TPS526CrossRefGoogle Scholar
  4. Alfano L, Guida T, Provitera L, Vecchio G, Billaud M, Santoro M et al (2010) RET is a Heat Shock Protein 90 (HSP90) client protein and is knocked down upon HSP90 pharmacological block. J Clin Endocrinol 95:3552–3557CrossRefGoogle Scholar
  5. Banerji U, O'Donnell A, Scurr M, Pacey S, Stapleton S, Asad Y et al (2005) Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol 23:4152–4161PubMedCrossRefPubMedCentralGoogle Scholar
  6. Barrott JJ, Hughes PF, Osada T, Yang XY, Hartman ZC, Loiselle DR et al (2013) Optical and radioiodinated tethered Hsp90 inhibitors reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells. Chem Biol 20:1187–1197PubMedCrossRefPubMedCentralGoogle Scholar
  7. Beere HM, Wolf BB, Cain K, Mosser DD, Mahboubi A, Kuwana T et al (2000) Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol 2:469–475PubMedCrossRefPubMedCentralGoogle Scholar
  8. Biamonte MA, Van de Water R, Arndt JW, Scannevin RH, Perret D, Lee WC (2010) Heat shock protein 90: inhibitors in clinical trials. J Med Chem 53:3–17PubMedCrossRefPubMedCentralGoogle Scholar
  9. Bonvini P, Gastaldi T, Falini B, Rosolen A (2002) Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), a novel Hsp90-client tyrosine kinase: down-regulation of NPM-ALK expression and tyrosine phosphorylation in ALK(+) CD30(+) lymphoma cells by the Hsp90 antagonist 17-allylamino,17-demethoxygeldanamycin. Cancer Res 62:1559–1566PubMedPubMedCentralGoogle Scholar
  10. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424CrossRefGoogle Scholar
  11. Breinig M, Mayer P, Harjung A, Goeppert B, Malz M, Penzel R et al (2011) Heat shock protein 90-sheltered overexpression of insulin-like growth factor 1 receptor contributes to malignancy of thymic epithelial tumors. Clin Cancer Res 17:2237–2249PubMedCrossRefPubMedCentralGoogle Scholar
  12. Burrows F, Zhang H, Kamal A (2004) Hsp90 activation and cell cycle regulation. Cell Cycle 3:1530–1536PubMedCrossRefPubMedCentralGoogle Scholar
  13. Caldas-Lopes E, Cerchietti L, Ahn JH, Clement CC, Robles AI, Rodina A et al (2009) Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. Proc Natl Acad Sci U S A 106:8368–8373PubMedPubMedCentralCrossRefGoogle Scholar
  14. Cameron DA, Spector N, Cortes J, Mano MS, Canon J-LR, Hickish T et al (2014) Targeting HSP90 in breast cancer: Enchant-1 (NCT01677455) phase 2 proof of concept study of ganetespib in first-line treatment of women with metastatic breast cancer. J Clin Oncol 32:TPS665CrossRefGoogle Scholar
  15. Chatterjee S, Burns TF (2017) Targeting heat shock proteins in cancer: a promising therapeutic approach. Int J Mol Sci 18:E1978PubMedCrossRefPubMedCentralGoogle Scholar
  16. Chatterjee S, Bhattacharya S, Socinski MA, Burns TF (2016) HSP90 inhibitors in lung cancer: promise still unfulfilled. Clin Adv Hematol Oncol 14:346–356PubMedPubMedCentralGoogle Scholar
  17. Chen Z, Sasaki T, Tan X, Carretero J, Shimamura T, Li D et al (2010) Inhibition of ALK, PI3K/MEK, and HSP90 in murine lung adenocarcinoma induced by EML4-ALK fusion oncogene. Cancer Res 70:9827–9836PubMedPubMedCentralCrossRefGoogle Scholar
  18. Chiosis G, Neckers L (2006) Tumor selectivity of Hsp90 inhibitors: the explanation remains elusive. ACS Chem Biol 1:279–284PubMedCrossRefPubMedCentralGoogle Scholar
  19. Daozhen C, Lu L, Min Y, Xinyu J, Ying H (2007) Synthesis of (131)I-labeled-[(131)I]iodo-17-allylamino-17-demethoxy geldanamycin ([(131)I]iodo-17-AAG) and its biodistribution in mice. Cancer Biother Radiopharm 22:607–612PubMedCrossRefPubMedCentralGoogle Scholar
  20. Do K, Speranza G, Chang L-C, Polley EC, Bishop R, Zhu W et al (2015) Phase I study of the heat shock protein 90 (Hsp90) inhibitor onalespib (AT13387) administered on a daily for 2 consecutive days per week dosing schedule in patients with advanced solid tumors. Investig New Drugs 33:921–930CrossRefGoogle Scholar
  21. Eccles SA, Massey A, Raynaud FI, Sharp SY, Box G, Valenti M et al (2008) NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. Cancer Res 68:2850–2860PubMedCrossRefPubMedCentralGoogle Scholar
  22. Eiseman JL, Lan J, Lagattuta TF, Hamburger DR, Joseph E, Covey JM et al (2005) 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 55:21–32PubMedCrossRefPubMedCentralGoogle Scholar
  23. Eroglu Z, Chen YA, Gibney GT, Weber JS, Kudchadkar RR, Khushalani NI et al (2018) Combined BRAF and HSP90 inhibition in patients with unresectable BRAF V600E-mutant melanoma. Clin Cancer Res 24:5516–5524PubMedCrossRefPubMedCentralGoogle Scholar
  24. Forsberg LK, Liu W, Holzbeierlein J, Blagg BSJ (2017) Modified biphenyl Hsp90 C-terminal inhibitors for the treatment of cancer. Bioorg Med Chem Lett 27:4514–4519PubMedPubMedCentralCrossRefGoogle Scholar
  25. Friedland JC, Smith DL, Sang J, Acquaviva J, He S, Zhang C et al (2014) Targeted inhibition of Hsp90 by ganetespib is effective across a broad spectrum of breast cancer subtypes. Investig New Drugs 32:14–24CrossRefGoogle Scholar
  26. Garon EB, Moran T, Barlesi F, Gandhi L, Sequist LV, Kim S-W et al (2012) Phase II study of the HSP90 inhibitor AUY922 in patients with previously treated, advanced non-small cell lung cancer (NSCLC). J Clin Oncol 30:7543–7543Google Scholar
  27. Garrido C, Schmitt E, Cande C, Vahsen N, Parcellier A, Kroemer G (2003) HSP27 and HSP70: potentially oncogenic apoptosis inhibitors. Cell Cycle 2:579–584PubMedCrossRefPubMedCentralGoogle Scholar
  28. Garrido C, Brunet M, Didelot C, Zermati Y, Schmitt E, Kroemer G (2006) Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties. Cell Cycle 5:2592–2601PubMedCrossRefPubMedCentralGoogle Scholar
  29. Georgakis GV, Li Y, Younes A (2006) The heat shock protein 90 inhibitor 17-AAG induces cell cycle arrest and apoptosis in mantle cell lymphoma cell lines by depleting cyclin D1, Akt, Bid and activating caspase 9. Br J Haematol 135:68–71PubMedCrossRefPubMedCentralGoogle Scholar
  30. Ghosh JC, Dohi T, Kang BH, Altieri DC (2008) Hsp60 regulation of tumor cell apoptosis. J Biol Chem 283:5188–5194PubMedCrossRefPubMedCentralGoogle Scholar
  31. Goetz MP, Toft D, Reid J, Ames M, Stensgard B, Safgren S et al (2005) Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. J Clin Oncol 23:1078–1087PubMedCrossRefGoogle Scholar
  32. Graham B, Curry J, Smyth T, Fazal L, Feltell R, Harada I et al (2012) The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non-small cell lung cancer. Cancer Sci 103:522–527PubMedCrossRefGoogle Scholar
  33. Graner MW (2016) Chapter eight – HSP90 and immune modulation in Cancer. In: Isaacs J, Whitesell L (eds) Advances in cancer research, vol 129. Elsevier Science & Technology, San Diego, pp 191–224Google Scholar
  34. Guo F, Rocha K, Bali P, Pranpat M, Fiskus W, Boyapalle S et al (2005) Abrogation of heat shock protein 70 induction as a strategy to increase antileukemia activity of heat shock protein 90 inhibitor 17-allylamino-demethoxy geldanamycin. Cancer Res 65:10536–10544PubMedCrossRefGoogle Scholar
  35. Hasenstein JR, Shin HC, Kasmerchak K, Buehler D, Kwon GS, Kozak KR (2012) Antitumor activity of Triolimus: a novel multidrug-loaded micelle containing Paclitaxel, Rapamycin, and 17-AAG. Mol Cancer Ther 11:2233–2242PubMedPubMedCentralCrossRefGoogle Scholar
  36. Hollingshead M, Alley M, Burger AM, Borgel S, Pacula-Cox C, Fiebig HH et al (2005) In vivo antitumor efficacy of 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride), a water-soluble geldanamycin derivative. Cancer Chemother Pharmacol 56:115–125PubMedCrossRefPubMedCentralGoogle Scholar
  37. Jensen MR, Schoepfer J, Radimerski T, Massey A, Guy CT, Brueggen J et al (2008) NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models. Breast Cancer Res 10:R33PubMedPubMedCentralCrossRefGoogle Scholar
  38. Jhaveri K, Taldone T, Modi S, Chiosis G (2012) Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers. Biochim Biophys Acta 1823:742–755PubMedCrossRefPubMedCentralGoogle Scholar
  39. Jhaveri K, Chandarlapaty S, Lake D, Gilewski T, Robson M, Goldfarb S et al (2014a) A phase II open-label study of ganetespib, a novel heat shock protein 90 inhibitor for patients with metastatic breast cancer. Clin Breast Cancer 14:154–160PubMedCrossRefGoogle Scholar
  40. Jhaveri K, Ochiana SO, Dunphy MP, Gerecitano JF, Corben AD, Peter RI et al (2014b) Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions. Expert Opin Investig Drugs 23:611–628PubMedPubMedCentralCrossRefGoogle Scholar
  41. Jhaveri K, Wang R, Teplinsky E, Chandarlapaty S, Solit D, Cadoo K et al (2017) A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer. Breast Cancer Res 19:89PubMedPubMedCentralCrossRefGoogle Scholar
  42. Kamal A, Thao L, Sensintaffar J, Zhang L, Boehm MF, Fritz LC et al (2003) A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425:407–410PubMedCrossRefPubMedCentralGoogle Scholar
  43. Kummar S, Gutierrez ME, Gardner ER, Chen X, Figg WD, Zajac-Kaye M et al (2010) 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 46:340–347PubMedCrossRefPubMedCentralGoogle Scholar
  44. Lamberti D, Cristinziano G, Porru M, Leonetti C, Egan JB, Shi CX et al (2018) HSP90 inhibition drives degradation of FGFR2 fusion proteins: implications for treatment of cholangiocarcinoma. Hepatology 69:131–142PubMedPubMedCentralGoogle Scholar
  45. Lancet JE, Gojo I, Burton M, Quinn M, Tighe SM, Kersey K et al (2010a) 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 24:699–705PubMedCrossRefPubMedCentralGoogle Scholar
  46. Lancet JE, Smith BD, Bradley R, Komrokji RS, Teofilovici F, Rizzieri DA (2010b) A phase I/II trial of the potent Hsp90 inhibitor STA-9090 administered once weekly in patients with advanced hematologic malignancies. Blood 116:3294–3294CrossRefGoogle Scholar
  47. Li J, Sun L, Xu C, Yu F, Zhou H, Zhao Y et al (2012) Structure insights into mechanisms of ATP hydrolysis and the activation of human heat-shock protein 90. Acta Biochim Biophys Sin Shanghai 44:300–306PubMedCrossRefPubMedCentralGoogle Scholar
  48. Marcu MG, Schulte TW, Neckers L (2000) Novobiocin and related coumarins and depletion of heat shock protein 90-dependent signaling proteins. J Natl Cancer Inst 92:242–248PubMedCrossRefPubMedCentralGoogle Scholar
  49. Mbofung RM, McKenzie JA, Malu S, Liu C, Peng W, Kuiatse I et al (2016) Abstract B105: HSP90 inhibitor, ganetespib, enhances responses to cancer immunotherapy through increased expression of interferon response genes. Cancer Immunol Res 4:B105Google Scholar
  50. McCarthy MM, Pick E, Kluger Y, Gould-Rothberg B, Lazova R, Camp RL et al (2008) HSP90 as a marker of progression in melanoma. Ann Oncol 19:590–594PubMedCrossRefPubMedCentralGoogle Scholar
  51. Meehan R, Kummar S, Do K, O’Sullivan Coyne G, Juwara L, Zlott J et al (2018) A phase I study of Ganetespib and Ziv-Aflibercept in patients with advanced carcinomas and sarcomas. Oncologist 23:1269–e1125PubMedPubMedCentralCrossRefGoogle Scholar
  52. Mimnaugh EG, Chavany C, Neckers L (1996) Polyubiquitination and proteasomal degradation of the p185c-erbB-2 receptor protein-tyrosine kinase induced by geldanamycin. J Biol Chem 271:22796–22801PubMedCrossRefPubMedCentralGoogle Scholar
  53. Miyajima N, Tsutsumi S, Sourbier C, Beebe K, Mollapour M, Rivas C et al (2013) The HSP90 inhibitor ganetespib synergizes with the MET kinase inhibitor crizotinib in both crizotinib-sensitive and -resistant MET-driven tumor models. Cancer Res 73:7022–7033PubMedCrossRefPubMedCentralGoogle Scholar
  54. Modi S, Stopeck A, Linden H, Solit D, Chandarlapaty S, Rosen N et al (2011) HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. Clin Cancer Res 17:5132–5139PubMedCrossRefPubMedCentralGoogle Scholar
  55. Modi S, Saura C, Henderson C, Lin NU, Mahtani R, Goddard J et al (2013) A multicenter trial evaluating retaspimycin HCL (IPI-504) plus trastuzumab in patients with advanced or metastatic HER2-positive breast cancer. Breast Cancer Res Treat 139:107–113PubMedPubMedCentralCrossRefGoogle Scholar
  56. Multhoff G, Pfister K, Gehrmann M, Hantschel M, Gross C, Hafner M et al (2001) A 14-mer Hsp70 peptide stimulates natural killer (NK) cell activity. Cell Stress Chaperones 6:337–344PubMedPubMedCentralCrossRefGoogle Scholar
  57. Neckers L, Workman P (2012) Hsp90 molecular chaperone inhibitors: are we there yet? Clin Cancer Res 18:64–76PubMedPubMedCentralCrossRefGoogle Scholar
  58. Normant E, Paez G, West KA, Lim AR, Slocum KL, Tunkey C et al (2011) The Hsp90 inhibitor IPI-504 rapidly lowers EML4-ALK levels and induces tumor regression in ALK-driven NSCLC models. Oncogene 30:2581–2586PubMedCrossRefPubMedCentralGoogle Scholar
  59. Obermann WM, Sondermann H, Russo AA, Pavletich NP, Hartl FU (1998) In vivo function of Hsp90 is dependent on ATP binding and ATP hydrolysis. J Cell Biol 143:901–910PubMedPubMedCentralCrossRefGoogle Scholar
  60. Ohkubo S, Kodama Y, Muraoka H, Hitotsumachi H, Yoshimura C, Kitade M et al (2015) TAS-116, a highly selective inhibitor of heat shock protein 90alpha and beta, demonstrates potent antitumor activity and minimal ocular toxicity in preclinical models. Mol Cancer Ther 14:14–22PubMedCrossRefPubMedCentralGoogle Scholar
  61. Pacey S, Wilson RH, Walton M, Eatock MM, Hardcastle A, Zetterlund A et al (2011) A phase I study of the heat shock protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced solid tumors. Clin Cancer Res 17:1561–1570PubMedPubMedCentralCrossRefGoogle Scholar
  62. Padmanabhan S, Kelly KR, Heaney M, Hodges S, Chanel S, Frattini M et al (2010) A phase I study of the potent Hsp90 inhibitor STA-9090 administered twice weekly in subjects with hematologic malignancies. Blood 116:2898–2898CrossRefGoogle Scholar
  63. Paraiso KH, Haarberg HE, Wood E, Rebecca VW, Chen YA, Xiang Y et al (2012) The HSP90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms. Clin Cancer Res 18:2502–2514PubMedPubMedCentralCrossRefGoogle Scholar
  64. Patel K, Wen J, Magliocca K, Muller S, Liu Y, Chen ZG et al (2014) Heat shock protein 90 (HSP90) is overexpressed in p16-negative oropharyngeal squamous cell carcinoma, and its inhibition in vitro potentiates the effects of chemoradiation. Cancer Chemother Pharmacol 74:1015–1022PubMedCrossRefPubMedCentralGoogle Scholar
  65. Pick E, Kluger Y, Giltnane JM, Moeder C, Camp RL, Rimm DL et al (2007) High HSP90 expression is associated with decreased survival in breast cancer. Cancer Res 67:2932–2937PubMedCrossRefPubMedCentralGoogle Scholar
  66. Powers MV, Clarke PA, Workman P (2008) Dual targeting of HSC70 and HSP72 inhibits HSP90 function and induces tumor-specific apoptosis. Cancer Cell 14:250–262PubMedCrossRefPubMedCentralGoogle Scholar
  67. Radons J (2016) The human HSP70 family of chaperones: where do we stand? Cell Stress Chaperones 21:379–404PubMedPubMedCentralCrossRefGoogle Scholar
  68. Ramalingam SS, Zaric B, Ceric T, Ciuleanu TE, Spicer JF, Bondarenko I et al (2014) Galaxy-2 trial (NCT01798485): a randomized phase 3 study of ganetespib in combination with docetaxel versus docetaxel alone in patients with advanced lung adenocarcinoma. J Clin Oncol 32:TPS8118CrossRefGoogle Scholar
  69. Ramalingam S, Goss G, Rosell R, Schmid-Bindert G, Zaric B, Andric Z et al (2015) A randomized phase II study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel in second-line therapy of advanced non-small cell lung cancer (GALAXY-1). Ann Oncol 26:1741–1748PubMedCrossRefPubMedCentralGoogle Scholar
  70. Rappa F, Farina F, Zummo G, David S, Campanella C, Carini F et al (2012) HSP-molecular chaperones in cancer biogenesis and tumor therapy: an overview. Anticancer Res 32:5139–5150PubMedPubMedCentralGoogle Scholar
  71. Ravagnan L, Gurbuxani S, Susin SA, Maisse C, Daugas E, Zamzami N et al (2001) Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nat Cell Biol 3:839–843PubMedCrossRefPubMedCentralGoogle Scholar
  72. Raveendran S, Rao A, Storkus W (2014) Combination immunotherapy of melanoma by inhibiting HSP90 and targeting its client proteins. (TUM7P.934). J Immunol 192:203.216Google Scholar
  73. Rerole AL, Jego G, Garrido C (2011) Hsp70: anti-apoptotic and tumorigenic protein. Methods Mol Biol 787:205–230PubMedCrossRefPubMedCentralGoogle Scholar
  74. Richardson PG, Chanan-Khan AA, Lonial S, Krishnan AY, Carroll MP, Alsina M et al (2011) Tanespimycin and bortezomib combination treatment in patients with relapsed or relapsed and refractory multiple myeloma: results of a phase 1/2 study. Br J Haematol 153:729–740PubMedCrossRefPubMedCentralGoogle Scholar
  75. Rodina A, Wang T, Yan P, Gomes ED, Dunphy MP, Pillarsetty N et al (2016) The epichaperome is an integrated chaperome network that facilitates tumour survival. Nature 538:397–401PubMedPubMedCentralCrossRefGoogle Scholar
  76. Ronnen EA, Kondagunta GV, Ishill N, Sweeney SM, Deluca JK, Schwartz L et al (2006) A phase II trial of 17-(Allylamino)-17-demethoxygeldanamycin in patients with papillary and clear cell renal cell carcinoma. Investig New Drugs 24:543–546CrossRefGoogle Scholar
  77. Saif MW, Takimoto C, Mita M, Banerji U, Lamanna N, Castro J et al (2014) A phase 1, dose-escalation, pharmacokinetic and Pharmacodynamic study of BIIB021 administered orally in patients with advanced solid tumors. Clin Cancer Res 20:445–455PubMedCrossRefPubMedCentralGoogle Scholar
  78. Saleh A, Srinivasula SM, Balkir L, Robbins PD, Alnemri ES (2000) Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat Cell Biol 2:476–483PubMedCrossRefPubMedCentralGoogle Scholar
  79. Sang J, Acquaviva J, Friedland JC, Smith DL, Sequeira M, Zhang C et al (2013) Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK inhibitor resistance in non-small cell lung cancer. Cancer Discov 3:430–443PubMedPubMedCentralCrossRefGoogle Scholar
  80. Schroder CP, Pedersen JV, Chua S, Swanton C, Akimov M, Ide S et al (2011) Use of biomarkers and imaging to evaluate the treatment effect of AUY922, an HSP90 inhibitor, in patients with HER2+ or ER+ metastatic breast cancer. J Clin Oncol 29:e11024CrossRefGoogle Scholar
  81. Sequist LV, Gettinger S, Senzer NN, Martins RG, Janne PA, Lilenbaum R et al (2010) Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer. J Clin Oncol 28:4953–4960PubMedPubMedCentralCrossRefGoogle Scholar
  82. Shapiro GI, Kwak E, Dezube BJ, Yule M, Ayrton J, Lyons J et al (2015) First-in-human phase I dose escalation study of a second-generation non-ansamycin HSP90 inhibitor, AT13387, in patients with advanced solid tumors. Clin Cancer Res 21:87–97PubMedCrossRefPubMedCentralGoogle Scholar
  83. Shi Y, Liu X, Lou J, Han X, Zhang L, Wang Q et al (2014) Plasma levels of heat shock protein 90 alpha associated with lung cancer development and treatment responses. Clin Cancer Res 20:6016–6022PubMedCrossRefPubMedCentralGoogle Scholar
  84. Socinski MA, Goldman J, El-Hariry I, Koczywas M, Vukovic V, Horn L et al (2013) A multicenter phase II study of ganetespib monotherapy in patients with genotypically defined advanced non-small cell lung cancer. Clin Cancer Res 19:3068–3077PubMedCrossRefPubMedCentralGoogle Scholar
  85. Soga S, Shiotsu Y, Akinaga S, Sharma SV (2003) Development of radicicol analogues. Curr Cancer Drug Targets 3:359–369PubMedCrossRefPubMedCentralGoogle Scholar
  86. Soga S, Akinaga S, Shiotsu Y (2013) Hsp90 inhibitors as anti-cancer agents, from basic discoveries to clinical development. Curr Pharm Des 19:366–376PubMedCrossRefPubMedCentralGoogle Scholar
  87. Solit DB, Osman I, Polsky D, Panageas KS, Daud A, Goydos JS et al (2008) Phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with metastatic melanoma. Clin Cancer Res 14:8302–8307PubMedPubMedCentralCrossRefGoogle Scholar
  88. Specht HM, Ahrens N, Blankenstein C, Duell T, Fietkau R, Gaipl US et al (2015) Heat Shock Protein 70 (Hsp70) peptide activated natural killer (NK) cells for the treatment of patients with non-small cell lung Cancer (NSCLC) after Radiochemotherapy (RCTx) – from preclinical studies to a clinical phase II trial. Front Immunol 6:162PubMedPubMedCentralCrossRefGoogle Scholar
  89. Speranza G, Anderson L, Chen AP, Do K, Eugeni M, Weil M et al (2018) First-in-human study of the epichaperome inhibitor PU-H71: clinical results and metabolic profile. Investig New Drugs 36:230–239CrossRefGoogle Scholar
  90. Straume O, Shimamura T, Lampa MJ, Carretero J, Oyan AM, Jia D et al (2012) Suppression of heat shock protein 27 induces long-term dormancy in human breast cancer. Proc Natl Acad Sci U S A 109:8699–8704PubMedPubMedCentralCrossRefGoogle Scholar
  91. Supko JG, Hickman RL, Grever MR, Malspeis L (1995) Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother Pharmacol 36:305–315PubMedCrossRefPubMedCentralGoogle Scholar
  92. Taipale M, Krykbaeva I, Koeva M, Kayatekin C, Westover KD, Karras GI et al (2012) Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 150:987–1001PubMedPubMedCentralCrossRefGoogle Scholar
  93. Vartholomaiou E, Echeverría PC, Picard D (2016) Chapter one – unusual suspects in the twilight zone between the Hsp90 interactome and carcinogenesis. In: Isaacs J, Whitesell L (eds) Advances in cancer research, vol 129. Academic, Cambridge, MA, pp 1–30Google Scholar
  94. Wagner AJ, Chugh R, Rosen LS, Morgan JA, George S, Gordon M et al (2013) A phase I study of the HSP90 inhibitor retaspimycin hydrochloride (IPI-504) in patients with gastrointestinal stromal tumors or soft-tissue sarcomas. Clin Cancer Res 19:6020–6029PubMedPubMedCentralCrossRefGoogle Scholar
  95. Wagner AJ, Agulnik M, Heinrich MC, Mahadevan D, Riedel RF, von Mehren M et al (2016) Dose-escalation study of a second-generation non-ansamycin HSP90 inhibitor, onalespib (AT13387), in combination with imatinib in patients with metastatic gastrointestinal stromal tumour. Eur J Cancer 61:94–101PubMedCrossRefPubMedCentralGoogle Scholar
  96. Wang X, Chen M, Zhou J, Zhang X (2014) HSP27, 70 and 90, anti-apoptotic proteins, in clinical cancer therapy (review). Int J Oncol 45:18–30PubMedCrossRefPubMedCentralGoogle Scholar
  97. Whitesell L, Lindquist SL (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5:761–772PubMedCrossRefGoogle Scholar
  98. Whitesell L, Sutphin PD, Pulcini EJ, Martinez JD, Cook PH (1998) The physical association of multiple molecular chaperone proteins with mutant p53 is altered by geldanamycin, an hsp90-binding agent. Mol Cell Biol 18:1517–1524PubMedPubMedCentralCrossRefGoogle Scholar
  99. Wu J, Liu T, Rios Z, Mei Q, Lin X, Cao S (2017) Heat shock proteins and cancer. Trends Pharmacol Sci 38:226–256PubMedCrossRefPubMedCentralGoogle Scholar
  100. Yao Q, Nishiuchi R, Li Q, Kumar AR, Hudson WA, Kersey JH (2003) FLT3 expressing leukemias are selectively sensitive to inhibitors of the molecular chaperone heat shock protein 90 through destabilization of signal transduction-associated kinases. Clin Cancer Res 9:4483–4493PubMedPubMedCentralGoogle Scholar
  101. Yufu Y, Nishimura J, Nawata H (1992) High constitutive expression of heat shock protein 90 alpha in human acute leukemia cells. Leuk Res 16:597–605PubMedCrossRefPubMedCentralGoogle Scholar
  102. Yuno A, Lee MJ, Lee S, Tomita Y, Rekhtman D, Moore B et al (2018) Clinical evaluation and biomarker profiling of Hsp90 inhibitors. Methods Mol Biol 1709:423–441PubMedCrossRefPubMedCentralGoogle Scholar
  103. Zhao H, Anyika M, Girgis A, Blagg BS (2014) Novologues containing a benzamide side chain manifest anti-proliferative activity against two breast cancer cell lines. Bioorg Med Chem Lett 24:3633–3637PubMedPubMedCentralCrossRefGoogle Scholar
  104. Zhou D, Liu Y, Ye J, Ying W, Ogawa LS, Inoue T et al (2013) A rat retinal damage model predicts for potential clinical visual disturbances induced by Hsp90 inhibitors. Toxicol Appl Pharmacol 273:401–409PubMedCrossRefPubMedCentralGoogle Scholar
  105. Zuehlke A, Johnson JL (2010) Hsp90 and co-chaperones twist the functions of diverse client proteins. Biopolymers 93:211–217PubMedPubMedCentralCrossRefGoogle Scholar

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Authors and Affiliations

  • Geraldine O’Sullivan Coyne
    • 1
  • Cecilia Monge
    • 1
  • Alice P. Chen
    • 1
    Email author
  1. 1.Division of Cancer Treatment and Diagnosis and Center for Cancer ResearchNational Cancer Institute, National Institutes of HealthBethesdaUSA

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