Skip to main content
SpringerLink
Log in

Combined HSP90 and kinase inhibitor therapy: Insights from The Cancer Genome Atlas

  • Perspective and Reflection Article
  • Published:
Cell Stress and Chaperones Aims and scope

Abstract

The merging of knowledge from genomics, cellular signal transduction and molecular evolution is producing new paradigms of cancer analysis. Protein kinases have long been understood to initiate and promote malignant cell growth and targeting kinases to fight cancer has been a major strategy within the pharmaceutical industry for over two decades. Despite the initial success of kinase inhibitors (KIs), the ability of cancer to evolve resistance and reprogram oncogenic signaling networks has reduced the efficacy of kinase targeting. The molecular chaperone HSP90 physically supports global kinase function while also acting as an evolutionary capacitor. The Cancer Genome Atlas (TCGA) has compiled a trove of data indicating that a large percentage of tumors overexpress or possess mutant kinases that depend on the HSP90 molecular chaperone complex. Moreover, the overexpression or mutation of parallel activators of kinase activity (PAKA) increases the number of components that promote malignancy and indirectly associate with HSP90. Therefore, targeting HSP90 is predicted to complement kinase inhibitors by inhibiting oncogenic reprogramming and cancer evolution. Based on this hypothesis, consideration should be given by both the research and clinical communities towards combining kinase inhibitors and HSP90 inhibitors (H90Ins) in combating cancer. The purpose of this perspective is to reflect on the current understanding of HSP90 and kinase biology as well as promote the exploration of potential synergistic molecular therapy combinations through the utilization of The Cancer Genome Atlas.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  • Abdel-Hafiz HA, Horwitz KB (2015) Role of epigenetic modifications in luminal breast cancer. Epigenomics 17:1–16

    Article  Google Scholar 

  • Acquaviva J, He S et al (2014a) mTOR inhibition potentiates HSP90 inhibitor activity via cessation of HSP synthesis. Mol Cancer Res 12(5):703–713

    Article  CAS  PubMed  Google Scholar 

  • Acquaviva J, Smith DL et al (2014b) Overcoming acquired BRAF inhibitor resistance in melanoma via targeted inhibition of HSP90 with ganetespib. Mol Cancer Ther 13(2):353–363

    Article  CAS  PubMed  Google Scholar 

  • Alarcon SV, Mollapour M et al (2012) Tumor-intrinsic and tumor-extrinsic factors impacting HSP90-targeted therapy. Curr Mol Med 12(9):1125–1141

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bagatell R, Paine-Murrieta GD et al (2000) Induction of a heat shock factor 1-dependent stress response alters the cytotoxic activity of HSP90-binding agents. Clin Cancer Res 6(8):3312–3318

    CAS  PubMed  Google Scholar 

  • Barrott JJ, Haystead TA (2013) HSP90, an unlikely ally in the war on cancer. Febs J 280(6):1381–1396

    Article  CAS  PubMed  Google Scholar 

  • B Besse, E. B., N.A. Pennell, A. Wozniak, D. Mahadevan, A. Spira, A. Oganesian, L. Manlapaz-Espiritu, H. Keer, J. Soria, D.R. Camidge. (2014). A study of Hsp90 inhibitor AT13387 alone and in combination with crizotinib (CZT) in the treatment of non-small cell lung cancer (NSCLC). Annals of Oncology (2014) 25 (suppl_4): iv426-iv470. 10.1093/annonc/mdu34. from http://oncologypro.esmo.org/Meeting-Resources/ESMO-2014/NSCLC-Metastatic/A-study-of-Hsp90-inhibitor-AT13387-alone-and-in-combination-with-crizotinib-CZT-in-the-treatment-of-non-small-cell-lung-cancer-NSCLC

  • Blagosklonny MV, Toretsky J et al (1996) Mutant conformation of p53 translated in vitro or in vivo requires functional HSP90. Proc Natl Acad Sci U S A 93(16):8379–8383

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411(6835):355–365

    Article  CAS  PubMed  Google Scholar 

  • Boussemart L, Malka-Mahieu H et al (2014) eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies. Nature 513(7516):105–109

    Article  CAS  PubMed  Google Scholar 

  • Brady SW, Zhang J et al (2015) PI3K-independent mTOR activation promotes lapatinib resistance and IAP expression that can be effectively reversed by mTOR and HSP90 inhibition. Cancer Biol Ther 16(3):402–411

    Article  PubMed  Google Scholar 

  • Burnett G, Kennedy EP (1954) The enzymatic phosphorylation of proteins. J Biol Chem 211(2):969–980

    CAS  PubMed  Google Scholar 

  • Calderwood SK (2013) Tumor heterogeneity, clonal evolution, and therapy resistance: an opportunity for multitargeting therapy. Discov Med 15(82):188–194

    PubMed Central  PubMed  Google Scholar 

  • Calderwood SK, Khaleque MA et al (2006) Heat shock proteins in cancer: chaperones of tumorigenesis. Trends Biochem Sci 31(3):164–172

    Article  CAS  PubMed  Google Scholar 

  • Calderwood SK, Xie Y et al (2010) Signal transduction pathways leading to heat shock transcription. Sign Transduct Insights 2:13–24

    Article  PubMed Central  PubMed  Google Scholar 

  • Carroll SB (2006) The making of the fittest: DNA and the ultimate forensic record of evolution. W.W. Norton & Co., New York

    Google Scholar 

  • Cerami E, Gao J et al (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2(5):401–404

    Article  PubMed  Google Scholar 

  • Chang EH, Furth ME et al (1982) Tumorigenic transformation of mammalian cells induced by a normal human gene homologous to the oncogene of Harvey murine sarcoma virus. Nature 297(5866):479–483

    Article  CAS  PubMed  Google Scholar 

  • Chen CT, Kim H et al (2012) MET activation mediates resistance to lapatinib inhibition of HER2-amplified gastric cancer cells. Mol Cancer Ther 11(3):660–669

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chen Z, Akbay E et al (2014) Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance. Clin Cancer Res 20(5):1204–1211

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chou SD, Prince T et al (2012) mTOR is essential for the proteotoxic stress response, HSF1 activation and heat shock protein synthesis. PLoS One 7(6):29

    Article  CAS  Google Scholar 

  • Ciocca DR, Arrigo AP et al (2013) Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update. Arch Toxicol 87(1):19–48

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Citri A, Alroy I et al (2002) Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy. Embo J 21(10):2407–2417

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Citri A, Harari D et al (2006) HSP90 recognizes a common surface on client kinases. J Biol Chem 281(20):14361–14369

    Article  CAS  PubMed  Google Scholar 

  • clinicaltrials.gov (2015). https://clinicaltrials.gov/ct2/results?term=hsp90+kinase+inhibitor&Search=Search

  • Collins FS, Varmus H (2015) A new initiative on precision medicine. N Engl J Med 372(9):793–795

    Article  CAS  PubMed  Google Scholar 

  • Dai C, Whitesell L et al (2007) Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 130(6):1005–1018

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Davies H, Bignell GR et al (2002) Mutations of the BRAF gene in human cancer. Nature 417(6892):949–954

    Article  CAS  PubMed  Google Scholar 

  • DeBerardinis RJ, Lum JJ et al (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7(1):11–20

    Article  CAS  PubMed  Google Scholar 

  • Di Fiore PP, Pierce JH et al (1987) erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science 237(4811):178–182

    Article  PubMed  Google Scholar 

  • Drake JM, Lee JK et al (2014) Clinical targeting of mutated and wild-type protein tyrosine kinases in cancer. Mol Cell Biol 34(10):1722–1732

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Druker BJ, Tamura S et al (1996) Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2(5):561–566

    Article  CAS  PubMed  Google Scholar 

  • Duesberg P, Stindl R et al (2001) Origin of multidrug resistance in cells with and without multidrug resistance genes: chromosome reassortments catalyzed by aneuploidy. Proc Natl Acad Sci U S A 98(20):11283–11288

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fang Q, Inanc B et al (2014) HSP90 regulates DNA repair via the interaction between XRCC1 and DNA polymerase beta. Nat Commun 5(5513)

  • Fauci AS, Folkers GK et al (2013) HIV-AIDS: much accomplished, much to do. Nat Immunol 14(11):1104–1107

    Article  CAS  PubMed  Google Scholar 

  • Fierro-Monti I, Echeverria P et al (2013) Dynamic impacts of the inhibition of the molecular chaperone HSP90 on the T cell proteome have implications for anti-cancer therapy. PLoS One 8(11)

  • Fischer EH, Graves DJ et al (1959) Structure of the site phosphorylated in the phosphorylase b to a reaction. J Biol Chem 234(7):1698–1704

    CAS  PubMed  Google Scholar 

  • Fiskus W, Verstovsek S et al (2011) Heat shock protein 90 inhibitor is synergistic with JAK2 inhibitor and overcomes resistance to JAK2-TKI in human myeloproliferative neoplasm cells. Clin Cancer Res 17(23):7347–7358

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Frei E 3rd, Holland JF et al (1958) A comparative study of two regimens of combination chemotherapy in acute leukemia. Blood 13(12):1126–1148

    PubMed  Google Scholar 

  • Fu Q, Wang PJ (2014) Mammalian piRNAs: biogenesis, function, and mysteries. Spermatogenesis 4:e27889, eCollection 2014

    Article  PubMed Central  PubMed  Google Scholar 

  • Fu J, Koul D et al (2013) Novel HSP90 inhibitor NVP-HSP990 targets cell-cycle regulators to ablate Olig2-positive glioma tumor-initiating cells. Cancer Res 73(10):3062–3074

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gangaraju VK, Yin H et al (2011) Drosophila Piwi functions in HSP90-mediated suppression of phenotypic variation. Nat Genet 43(2):153–158

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gao J, Aksoy BA et al (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6(269):2004088

    Article  CAS  Google Scholar 

  • Garraway LA, Janne PA (2012) Circumventing cancer drug resistance in the era of personalized medicine. Cancer Discov 2(3):214–226

    Article  CAS  PubMed  Google Scholar 

  • Gerlinger M, McGranahan N et al (2014) Cancer: evolution within a lifetime. Annu Rev Genet 48:215–236

    Article  CAS  PubMed  Google Scholar 

  • Grammatikakis N, Vultur A et al (2002) The role of HSP90N, a new member of the HSP90 family, in signal transduction and neoplastic transformation. J Biol Chem 277(10):8312–8320

    Article  CAS  PubMed  Google Scholar 

  • Gray PJ Jr, Prince T et al (2008) Targeting the oncogene and kinome chaperone CDC37. Nat Rev Cancer 8(7):491–495

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Greenman C, Stephens P et al (2007) Patterns of somatic mutation in human cancer genomes. Nature 446(7132):153–158

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Grenert JP, Sullivan WP et al (1997) The amino-terminal domain of heat shock protein 90 (HSP90) that binds geldanamycin is an ATP/ADP switch domain that regulates HSP90 conformation. J Biol Chem 272(38):23843–23850

    Article  CAS  PubMed  Google Scholar 

  • Guettouche T, Boellmann F et al (2005) Analysis of phosphorylation of human heat shock factor 1 in cells experiencing a stress. BMC Biochem 6:4

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Hadziselimovic F, Hadziselimovic NO et al (2015) Piwi-pathway alteration induces LINE-1 transposon derepression and infertility development in cryptorchidism. Sex Dev 9(2):98–104

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    Article  CAS  PubMed  Google Scholar 

  • Hashida S, Yamamoto H et al (2015) HSP90 inhibitor NVP-AUY922 enhances the radiation sensitivity of lung cancer cell lines with acquired resistance to EGFR-tyrosine kinase inhibitors. Oncol Rep 33(3):1499–1504

    PubMed  Google Scholar 

  • Hiley CT, Swanton C (2014) Spatial and temporal cancer evolution: causes and consequences of tumour diversity. Clin Med 14(6):14–16

    Google Scholar 

  • Hill VK, Ricketts C et al (2011) Genome-wide DNA methylation profiling of CpG islands in breast cancer identifies novel genes associated with tumorigenicity. Cancer Res 71(8):2988–2999

    Article  CAS  PubMed  Google Scholar 

  • Hingorani SR, Wang L et al (2005) Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7(5):469–483

    Article  CAS  PubMed  Google Scholar 

  • Holmberg CI, Tran SE et al (2002) Multisite phosphorylation provides sophisticated regulation of transcription factors. Trends Biochem Sci 27(12):619–627

    Article  CAS  PubMed  Google Scholar 

  • Huang W, Wu QD et al (2015) Novel HSP90 inhibitor FW-04-806 displays potent antitumor effects in HER2-positive breast cancer cells as a single agent or in combination with lapatinib. Cancer Lett 356(2 Pt B):862–871

    Article  CAS  PubMed  Google Scholar 

  • Hubbard, S. (2014). Exelixis announces positive preliminary data from an investigator-sponsored phase 1 trial of XL888 and vemurafenib. from http://finance.yahoo.com/news/exelixis-announces-positive-preliminary-data-092000599.html

  • Hudziak RM, Schlessinger J et al (1987) Increased expression of the putative growth factor receptor p185HER2 causes transformation and tumorigenesis of NIH 3T3 cells. Proc Natl Acad Sci U S A 84(20):7159–7163

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ichiyanagi T, Ichiyanagi K et al (2014) HSP90 alpha plays an important role in piRNA biogenesis and retrotransposon repression in mouse. Nucleic Acids Res 42(19):11903–11911

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Izumi N, Kawaoka S et al (2013) HSP90 facilitates accurate loading of precursor piRNAs into Piwi proteins. RNA 19(7):896–901

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jhaveri K, Taldone T et al (2012) Advances in the clinical development of heat shock protein 90 (HSP90) inhibitors in cancers. Biochim Biophys Acta 3:742–755

    Article  CAS  Google Scholar 

  • Johnson ML, Yu HA et al (2015) Phase I/II study of HSP90 Inhibitor AUY922 and erlotinib for EGFR-mutant lung cancer with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors. J Clin Oncol 13(59)

  • Kamal A, Thao L et al (2003) A high-affinity conformation of HSP90 confers tumour selectivity on HSP90 inhibitors. Nature 425(6956):407–410

    Article  CAS  PubMed  Google Scholar 

  • Kaplan AL, Litwin MS et al (2014) The future of bladder cancer care in the USA. Nat Rev Urol 11(1):59–62

    Article  PubMed  Google Scholar 

  • Katayama R, Khan TM et al (2011) Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A 108(18):7535–7540

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Klinge CM (2015) miRNAs regulated by estrogens, tamoxifen, and endocrine disruptors and their downstream gene targets. Mol Cell Endocrinol

  • Knight ZA, Shokat KM (2005) Features of selective kinase inhibitors. Chem Biol 12(6):621–637

    Article  CAS  PubMed  Google Scholar 

  • Konicek BW, Dumstorf CA et al (2008) Targeting the eIF4F translation initiation complex for cancer therapy. Cell Cycle 7(16):2466–2471

    Article  CAS  PubMed  Google Scholar 

  • Lachowiec J, Lemus T et al (2015) HSP90 promotes kinase evolution. Mol Biol Evol 32(1):91–99

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lee AJ, Endesfelder D et al (2011) Chromosomal instability confers intrinsic multidrug resistance. Cancer Res 71(5):1858–1870

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lee YY, Kim HP et al (2013) Phosphoproteomic analysis identifies activated MET-axis PI3K/AKT and MAPK/ERK in lapatinib-resistant cancer cell line. Exp Mol Med 22(45):115

    Google Scholar 

  • Lerdrup M, Hommelgaard AM et al (2006) Geldanamycin stimulates internalization of ErbB2 in a proteasome-dependent way. J Cell Sci 119(Pt 1):85–95

    Article  CAS  PubMed  Google Scholar 

  • Levinson AD, Oppermann H et al (1978) Evidence that the transforming gene of avian sarcoma virus encodes a protein kinase associated with a phosphoprotein. Cell 15(2):561–572

    Article  CAS  PubMed  Google Scholar 

  • Linehan WM, Rouault TA (2013) Molecular pathways: fumarate hydratase-deficient kidney cancer—targeting the Warburg effect in cancer. Clin Cancer Res 19(13):3345–3352

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Liu H, Lu J et al (2015) Targeting heat-shock protein 90 with ganetespib for molecularly targeted therapy of gastric cancer. Cell Death Dis 15(6):555

    Google Scholar 

  • Lu X, Wang L et al (2012a) HSP90 inhibitors and the reduction of anti-cancer drug resistance by non-genetic and genetic mechanisms. Pharmaceuticals (Basel) 5(9):890–898

    Article  CAS  Google Scholar 

  • Lu X, Xiao L et al (2012b) HSP90 inhibitors and drug resistance in cancer: the potential benefits of combination therapies of HSP90 inhibitors and other anti-cancer drugs. Biochem Pharmacol 83(8):995–1004

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ma Y, Zeng S et al (2002) The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations. Blood 99(5):1741–1744

    Article  CAS  PubMed  Google Scholar 

  • Manjarrez JR, Sun L et al (2014) HSP90-dependent assembly of the DBC2/RhoBTB2-Cullin3 E3-ligase complex. PLoS One 9(3)

  • Manning G, Whyte DB et al (2002) The protein kinase complement of the human genome. Science 298(5600):1912–1934

    Article  CAS  PubMed  Google Scholar 

  • Maroun CR, Rowlands T (2014) The MET receptor tyrosine kinase: a key player in oncogenesis and drug resistance. Pharmacol Ther 142(3):316–338

    Article  CAS  PubMed  Google Scholar 

  • Mendillo ML, Santagata S et al (2012) HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers. Cell 150(3):549–562

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Methot SP, Litzler LC et al (2015) Consecutive interactions with HSP90 and eEF1A underlie a functional maturation and storage pathway of AID in the cytoplasm. J Exp Med 212(4):581–596

    Article  CAS  PubMed  Google Scholar 

  • Miyajima N, Tsutsumi S 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(23):7022–7033

    Article  CAS  PubMed  Google Scholar 

  • Miyata Y, Nakamoto H et al (2013) The therapeutic target HSP90 and cancer hallmarks. Curr Pharm Des 19(3):347–365

    Article  CAS  PubMed  Google Scholar 

  • Moses MA, Henry EC et al (2015) The heat shock protein 90 inhibitor, (-)-epigallocatechin gallate, has anticancer activity in a novel human prostate cancer progression model. Cancer Prev Res 8(3):249–257

    Article  CAS  Google Scholar 

  • Moulick K, Ahn JH et al (2011) Affinity-based proteomics reveal cancer-specific networks coordinated by HSP90. Nat Chem Biol 7(11):818–826

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nagata Y, Anan T et al (1999) The stabilization mechanism of mutant-type p53 by impaired ubiquitination: the loss of wild-type p53 function and the HSP90 association. Oncogene 18(44):6037–6049

    Article  CAS  PubMed  Google Scholar 

  • Nagatsuma AK, Aizawa M et al (2014) Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma. Gastric Cancer

  • Neckers L, Trepel JB (2014) Stressing the development of small molecules targeting HSP90. Clin Cancer Res 20(2):275–277

    Article  CAS  PubMed  Google Scholar 

  • Neckers L, Workman P (2012) HSP90 molecular chaperone inhibitors: are we there yet? Clin Cancer Res 18(1):64–76

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nony P, Gaude H et al (2003) Stability of the Peutz-Jeghers syndrome kinase LKB1 requires its binding to the molecular chaperones HSP90/Cdc37. Oncogene 22(57):9165–9175

    Article  CAS  PubMed  Google Scholar 

  • O’Connell BC, O’Callaghan K et al (2014) HSP90 inhibition enhances antimitotic drug-induced mitotic arrest and cell death in preclinical models of non-small cell lung cancer. PLoS One 9(12)

  • Ohkubo S, Kodama Y et al (2015) TAS-116, a highly selective inhibitor of heat shock protein 90 alpha and beta, demonstrates potent antitumor activity and minimal ocular toxicity in preclinical models. Mol Cancer Ther 14(1):14–22

    Article  CAS  PubMed  Google Scholar 

  • Ou SH, Kwak EL et al (2011) Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. J Thorac Oncol 6(5):942–946

    Article  PubMed  Google Scholar 

  • Pao W, Miller VA et al (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2(3):22

    Article  CAS  Google Scholar 

  • Pelletier J, Graff J et al (2015) Targeting the eIF4F translation initiation complex: a critical nexus for cancer development. Cancer Res 75(2):250–263

    Article  CAS  PubMed  Google Scholar 

  • Powell E, Piwnica-Worms D et al (2014) Contribution of p53 to metastasis. Cancer Discov 4(4):405–414

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pratt WB, Toft DO (2003) Regulation of signaling protein function and trafficking by the HSP90/HSP70-based chaperone machinery. Exp Biol Med 228(2):111–133

    CAS  Google Scholar 

  • Prince T, Matts RL (2004) Definition of protein kinase sequence motifs that trigger high affinity binding of HSP90 and Cdc37. J Biol Chem 279(38):39975–39981

    Article  CAS  PubMed  Google Scholar 

  • Prodromou C (2009) Strategies for stalling malignancy: targeting cancer’s addiction to HSP90. Curr Top Med Chem 9(15):1352–1368

    Article  CAS  PubMed  Google Scholar 

  • Prodromou C, Roe SM et al (1997) Identification and structural characterization of the ATP/ADP-binding site in the HSP90 molecular chaperone. Cell 90(1):65–75

    Article  CAS  PubMed  Google Scholar 

  • Ricketts CJ, Hill VK et al (2014) Tumor-specific hypermethylation of epigenetic biomarkers, including SFRP1, predicts for poorer survival in patients from the TCGA Kidney Renal Clear Cell Carcinoma (KIRC) project. PLoS One 9(1)

  • Roskoski, R. (2015). “http://www.brimr.org/.” from http://www.brimr.org/PKI/PKIs.htm

  • Rutherford SL, Lindquist S (1998) HSP90 as a capacitor for morphological evolution. Nature 396(6709):336–342

    Article  CAS  PubMed  Google Scholar 

  • Sang J, Acquaviva J et al (2013) Targeted inhibition of the molecular chaperone HSP90 overcomes ALK inhibitor resistance in non-small cell lung cancer. Cancer Discov 3(4):430–443

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Santagata S, Mendillo ML et al (2013) Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state. Science 341(6143):1238303

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Sequist LV, Gettinger S 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(33):4953–4960

    Article  CAS  PubMed  Google Scholar 

  • Sessa C, Shapiro GI et al (2013) First-in-human phase I dose-escalation study of the HSP90 inhibitor AUY922 in patients with advanced solid tumors. Clin Cancer Res 19(13):3671–3680

    Article  CAS  PubMed  Google Scholar 

  • Shao J, Grammatikakis N et al (2001) HSP90 regulates p50(cdc37) function during the biogenesis of the active conformation of the heme-regulated eIF2 alpha kinase. J Biol Chem 276(1):206–214

    Article  CAS  PubMed  Google Scholar 

  • Shattuck DL, Miller JK et al (2008) Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells. Cancer Res 68(5):1471–1477

    Article  CAS  PubMed  Google Scholar 

  • Shetzer Y, Solomon H et al (2014) The paradigm of mutant p53-expressing cancer stem cells and drug resistance. Carcinogenesis 35(6):1196–1208

    Article  CAS  PubMed  Google Scholar 

  • Shimamura T, Lowell AM et al (2005) Epidermal growth factor receptors harboring kinase domain mutations associate with the heat shock protein 90 chaperone and are destabilized following exposure to geldanamycins. Cancer Res 65(14):6401–6408

    Article  CAS  PubMed  Google Scholar 

  • Shimamura T, Li D et al (2008) HSP90 inhibition suppresses mutant EGFR-T790M signaling and overcomes kinase inhibitor resistance. Cancer Res 68(14):5827–5838

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sjoblom T, Jones S et al (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314(5797):268–274

    Article  PubMed  CAS  Google Scholar 

  • Solarova Z, Mojzis J et al (2015) HSP90 inhibitor as a sensitizer of cancer cells to different therapies (review). Int J Oncol 46(3):907–926

    PubMed  Google Scholar 

  • Solier S, Kohn KW et al (2012) Heat shock protein 90 alpha (HSP90 alpha), a substrate and chaperone of DNA-PK necessary for the apoptotic response. Proc Natl Acad Sci U S A 109(32):12866–12872

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sollars V, Lu X et al (2003) Evidence for an epigenetic mechanism by which HSP90 acts as a capacitor for morphological evolution. Nat Genet 33(1):70–74

    Article  CAS  PubMed  Google Scholar 

  • Specchia V, Piacentini L et al (2010) HSP90 prevents phenotypic variation by suppressing the mutagenic activity of transposons. Nature 463(7281):662–665

    Article  CAS  PubMed  Google Scholar 

  • Suzuki R, Hideshima T et al (2015) Anti-tumor activities of selective HSP90 alpha/beta inhibitor, TAS-116, in combination with bortezomib in multiple myeloma. Leukemia 29(2):510–514. doi:10.1038/leu.2014.300, Epub 2014 Oct 13

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Taipale M, Jarosz DF et al (2010) HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat Rev Mol Cell Biol 11(7):515–528

    Article  CAS  PubMed  Google Scholar 

  • Taipale M, Krykbaeva I et al (2012) Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 150(5):987–1001

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Taipale M, Tucker G et al (2014) A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways. Cell 158(2):434–448

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Taldone T, Ochiana SO et al (2014) Selective targeting of the stress chaperome as a therapeutic strategy. Trends Pharmacol Sci 35(11):592–603

    Article  CAS  PubMed  Google Scholar 

  • Tang Z, Dai S et al (2015) MEK guards proteome stability and inhibits tumor-suppressive amyloidogenesis via HSF1. Cell 160(4):729–744

    Article  CAS  PubMed  Google Scholar 

  • Tauchi T, Okabe S et al (2011) Combined effects of novel heat shock protein 90 inhibitor NVP-AUY922 and nilotinib in a random mutagenesis screen. Oncogene 30(24):2789–2797

    Article  CAS  PubMed  Google Scholar 

  • Tonini G (2015) Trends in the early investigational drug development and areas for improvement. Expert Opin Investig Drugs 20:1–6

    Google Scholar 

  • Trepel J, Mollapour M et al (2010) Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 10(8):537–549

    Article  CAS  PubMed  Google Scholar 

  • Vaidya S, Vundinti BR et al (2015) Evolution of BCR/ABL gene mutation in CML is time dependent and dependent on the pressure exerted by tyrosine kinase inhibitor. PLoS One 10(1)

  • Wachsberger PR, Lawrence YR et al (2014) HSP90 inhibition enhances PI-3 kinase inhibition and radiosensitivity in glioblastoma. J Cancer Res Clin Oncol 140(4):573–582

    Article  CAS  PubMed  Google Scholar 

  • Walerych D, Kudla G et al (2004) HSP90 chaperones wild-type p53 tumor suppressor protein. J Biol Chem 279(47):48836–48845

    Article  CAS  PubMed  Google Scholar 

  • Walerych D, Napoli M et al (2012) The rebel angel: mutant p53 as the driving oncogene in breast cancer. Carcinogenesis 33(11):2007–2017

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ward PS, Thompson CB (2012) Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell 21(3):297–308

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ward A, Shukla K et al (2014) MicroRNA-519a is a novel oncomir conferring tamoxifen resistance by targeting a network of tumour-suppressor genes in ER+ breast cancer. J Pathol 233(4):368–379

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Whitesell L, Lindquist SL (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5(10):761–772

    Article  CAS  PubMed  Google Scholar 

  • Whitesell L, Mimnaugh EG et al (1994) Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci U S A 91(18):8324–8328

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Whitesell L, Santagata S et al (2014) HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models. Proc Natl Acad Sci U S A 111(51):18297–18302

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wong AJ, Bigner SH et al (1987) Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci U S A 84(19):6899–6903

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Workman P, Burrows F et al (2007a) Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Ann N Y Acad Sci 1113:202–216

    Article  CAS  PubMed  Google Scholar 

  • Xiao L, Rasouli P et al (2007) Possible effects of early treatments of HSP90 inhibitors on preventing the evolution of drug resistance to other anti-cancer drugs. Curr Med Chem 14(2):223–232

    Article  CAS  PubMed  Google Scholar 

  • Xu W, Marcu M et al (2002) Chaperone-dependent E3 ubiquitin ligase CHIP mediates a degradative pathway for c-ErbB2/Neu. Proc Natl Acad Sci U S A 99(20):12847–12852

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xu W, Yuan X et al (2005) Surface charge and hydrophobicity determine ErbB2 binding to the HSP90 chaperone complex. Nat Struct Mol Biol 12(2):120–126

    Article  CAS  PubMed  Google Scholar 

  • Yu HA, Riely GJ et al (2014) Therapeutic strategies utilized in the setting of acquired resistance to EGFR tyrosine kinase inhibitors. Clin Cancer Res 20(23):5898–5907

    Article  CAS  PubMed  Google Scholar 

  • Yuan TL, Cantley LC (2008) PI3K pathway alterations in cancer: variations on a theme. Oncogene 27(41):5497–5510

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhao RX, Xu ZX (2014) Targeting the LKB1 tumor suppressor. Curr Drug Targets 15(1):32–52

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhao R, Davey M et al (2005) Navigating the chaperone network: an integrative map of physical and genetic interactions mediated by the HSP90 chaperone. Cell 120(5):715–727

    Article  CAS  PubMed  Google Scholar 

  • Zhao Y, Polley EC et al (2015) GeneMed: an informatics hub for the coordination of next-generation sequencing studies that support precision oncology clinical trials. Cancer Inform 14(Suppl 2):45–55

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Jane Trepel, Young Lee, and Chris Ricketts for thoughtful scientific discussion. This work was supported by funds from the Intramural Research Program, National Cancer Institute. We sincerely regret that we were not able to include all the references and sources that influenced or provided the scientific foundation for this manuscript.

Supplemental Tables 2 and 3 provide the sources for making Table 1 and Supplemental Table 1. Supplemental Tables 4 and 5 list the current information on clinical trials using H90Ins.

Author information

Authors and Affiliations

  1. Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, USA

    Harvey Schwartz, Brad Scroggins, Abbey Zuehlke, Toshiki Kijima, Kristin Beebe, Alok Mishra, Len Neckers & Thomas Prince

Authors
  1. Harvey Schwartz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brad Scroggins
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abbey Zuehlke
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Toshiki Kijima
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kristin Beebe
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alok Mishra
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Len Neckers
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Thomas Prince
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas Prince.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(XLSX 92 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schwartz, H., Scroggins, B., Zuehlke, A. et al. Combined HSP90 and kinase inhibitor therapy: Insights from The Cancer Genome Atlas. Cell Stress and Chaperones 20, 729–741 (2015). https://doi.org/10.1007/s12192-015-0604-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12192-015-0604-1

Keywords

Search

Navigation